PROCESS FOR PREPARING FILLED HARD-SHELL CAPSULES WITH (METH)ACRYLATE COPOLYMER BASED COATINGS WITH A CAPSULE-FILLING MACHINE

Abstract

A process can be used for preparing a polymer coated hard-shell capsule, filled with a fill containing a biologically active ingredient. The hard-shell capsule contains a body and a cap, and in a closed state, the cap overlaps the body either in a pre-locked state or in a final-locked state. The material of the body and the cap contains an ethyl-, methyl-, or propyl-ether of cellulose, starch, or pullulan. The hard-shell capsule is coated with a coating layer that covers the hard-shell capsule in the pre-locked state. The coating layer contains one or more (meth)acrylate copolymers, where the coating layer is present in an amount of about 1 to 5.8 mg/cm.sup.2. The process involves providing the polymer-coated hard-shell capsule in the pre-locked state to a capsule-filling machine, separating the body and the cap, filling the body with the fill, and rejoining the body and the cap in the final-locked state.

Claims

1-16. (canceled)

17: A process for preparing a polymer coated hard-shell capsule, the process comprising: providing a hard-shell capsule comprising a body and a cap in a pre-locked state, coating the hard-shell capsule in the pre-locked state with a coating solution, suspension, or dispersion comprising one or more (meth)acrylate copolymers having a glass transition temperature from −10° C. to 115° C. as determined by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05, to obtain a coating layer on the hard-shell capsule, and optionally, drying the coated hard-shell capsule, wherein a material of the body and the cap is selected from the group consisting of ethyl ether of cellulose, methyl ether of cellulose, propyl ether of cellulose, starch, and pullulan, wherein the coating layer is present in an amount of about 1 to 5.8 mg/cm.sup.2, and wherein a dried film of the coating solution, suspension, or dispersion having a thickness of 250 μm, has an elongation at break of about 15 to 500%.

18: The process according to claim 17, wherein the material of the body and the cap comprises hydroxypropyl methyl cellulose.

19: The process according to claim 17, wherein the one or more (meth)acrylate copolymers is selected from the group consisting of a copolymer of methacrylic acid and ethyl acrylate; a copolymer of methacrylic acid and methyl methacrylate; a copolymer of ethyl acrylate and methyl methacrylate; a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate; a mixture of a copolymer of methacylic acid and ethyl acrylate, with a copolymer of methyl methacrylate and ethyl acrylate; and a mixture of a copolymer of methacrylic acid, methyl acrylate, and methyl methacrylate, with a copolymer of methyl methacrylate and ethyl acrylate.

20: The process according to claim 17, wherein the coating layer comprises a (meth)acrylate copolymer comprising polymerized units of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate.

21: The process according to claim 17, wherein the coating layer comprises a (meth)acrylate copolymer comprising polymerized units of 60 to 80% by weight of ethyl acrylate and 40 to 20% by weight of methyl methacrylate.

22: The process according to claim 17, wherein the coating layer comprises a (meth)acrylate copolymer comprising polymerized units of 5 to 15% by weight of methacrylic acid, 60 to 70% by weight of methyl acrylate, and 20 to 30% by weight of methyl methacrylate.

23: The process according to claim 17, wherein the coating layer comprises a mixture of (meth)acrylate copolymers comprising polymerized units of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate; and a (meth)acrylate copolymer comprising polymerized units of 60 to 80% by weight of ethyl acrylate and 40 to 20% by weight of methyl methacrylate; at a ratio from 10:1 to 1:10 by weight.

24: The process according to claim 17, wherein the coating layer comprises a mixture of (meth)acrylate copolymers comprising polymerized units of 5 to 15% by weight of methacrylic acid, 60 to 70% by weight of methyl acrylate, and 20 to 30% by weight of methyl methacrylate; and a (meth)acrylate copolymer comprising polymerized units of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate; at a ratio from 1:1 to 5:1 by weight.

25: The process according to claim 17, wherein the coating layer comprises 2-50% by weight of one or more plasticizers.

26: The process according to claim 25, wherein the one or more plasticizers is selected from the group consisting of alkyl citrate, glycerol ester, alkyl phthalate, alkyl sebacate, sucrose ester, sorbitan ester, glycerol, propylene glycol, and polyethylene glycol.

27: The process according to claim 17, wherein the coating layer comprises 50 to 100% by weight of the one or more (meth)acrylate copolymers and 50 to 0% by weight of pharmaceutical or nutraceutical excipients.

28: The process according to claim 27, wherein the pharmaceutical or nutraceutical excipients comprises one or more detacking agents.

29: The process according to claim 28, wherein the one or more detacking agents is selected from the group consisting of Ca-stearate, Mg-stearate, glycerol monostearate, and talc.

30: The process according to claim 17, wherein the coating layer comprises an emulsifier.

31: The process according to claim 30, wherein an amount of the emulsifier is in a range of 1 to 30% by weight calculated based on a weight of the one or more (meth)acrylate copolymers.

32: The process according to claim 30, wherein the emulsifier is polysorbate 80.

33: The process according to claim 17, wherein the coating layer is present in an amount of about 2 to 5 mg/cm.sup.2.

Description

EXAMPLES

[0123] Elongation at break values of dried films corresponding to the composition of the coating layer of examples 1 to 7.

[0124] Elongation at break may be determined according to DIN EN ISO 527-3:2019-02, determination of tensile properties for plastic foils and sheets with a thickness below 1.000 μm. The elongation at break is the percentage Increase in length that a material will achieve before breaking. This figure is shown as the percentage. Suspension of the compositions for the coating layer are spread on a glass plate and dried to a film of 250 μm thickness. The elongation at break is determined with these samples according to DIN EN ISO 527-3:2019-02.

[0125] Example for the Preparation and Testing of Polymer Films:

[0126] Formulation:

[0127] Polymer dispersion 30 g=9 g solids, used for a 250 μm film after drying.

[0128] Equipment:

[0129] Glass plate 20 cm×20 cm with a surrounding of 1 cm glass strips of 0.5-0.7 cm height, resulting in a free preparation area of 361 cm.sup.2. This glass plate is in addition covered with a self-adhesive Polytetrafluoroethylen foil (i.e. Tygaflor®).

[0130] Processing:

[0131] The polymer and diluent are mixed on a magnetic stirrer for 10 minutes at low speed. The polymer solution or suspension needs to be air free to avoid voids in the polymer foil. The Polytetrafluoroethylen covered glass plate is levelled in an oven and the polymer solution or dispersion is poured into it. The mixture is dried for approximately 4 days at 40° C. After drying the foils or sheets will be conditioned for 16 hours at 23° C. and 50% relative humidity.

[0132] The resulting film thickness is approx. 250 μm.

[0133] The same method can be used to manufacture films or coating suspensions. In this case the coating suspension is prepared like usually (e.g. using an ultra turrax). An aliquot amount for 9 g of total solids (including formulation excipients) is diluted with demineralized water up to a total amount of 100 g.

[0134] Results

TABLE-US-00001 Coating Elongation layer at break Example [mg/cm2] [%] Process 1 Inventive 3.6 ca. 70 Pre-coated capsules, capsule filling machine 2 Comparative 3.6 ca. 70 Uncoated capsules, capsule filling machine, post-coating 3 Comparative 6.0 ca. 70 Pre-coated capsules, capsule filling machine 4 Inventive 3.3 ca. 30 Pre-coated capsules, capsule filling machine 5 Comparative 3.3 ca. 30 Uncoated capsules, capsule filling machine, post-coating 6 Inventive 2.9 ca. 70 Pre-coated capsules, capsule filling machine 7 Comparative 2.8 ca. 5  Pre-coated capsules, capsule filling machine

Example 1 (Inventive)—Enteric Coating of EUDRAGIT® L 30D-55 and EUDRAGIT® NM 30D Combination on Pre-Locked Capsules in Drum Coater and Automatic Capsule Filling

[0135] The EUDRAGIT® polymer(s) were mixed in a suitable sized container. The additional excipients were added into the water while gently stirring. After a suitable post stirring time the excipient suspension was added to the polymer dispersion. The spraying suspension was gently stirred during the coating process. The capsules were coated in the pre-locked state utilizing a drum coater.

TABLE-US-00002 TABLE 1 Formulation Example 1 - Coating on Kcaps ® HPMC Size 0 capsules (Batch size 90 g i.e. 833 capsules) Solid Composition Material Composition Percentage EUDRAGIT ® L 30 D-55 2.7 mg/cm.sup.2 75.0% EUDRAGIT ® NM 30D 0.3 mg/cm.sup.2 8.33% Triethyl citrate 20% on ds* 16.67% Demineralized water On demand n/a Solid content 10% w/w Total solid weight gain 3.6 mg/cm.sup.2 *Quantity based on dry polymer substance [% j

TABLE-US-00003 TABLE 2 Process Parameter Example 1 Parameter Value Machine Neocota 5D Batch size [g] 90   Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat pattern pressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.] 50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 33-38 Exhaust air temperature [° C.] 28-31 Product temperature [° C.] 28-29 Spray rate [g/min/kg]  8-16 Process time [min] 190.sub.  

[0136] Encapsulation Parameter

[0137] 557 mg of Omeprazole pellets (5% Omeprazole) were filled into the polymer coated pre-locked capsules using an automatic Capsule filling equipment AFTLAB, ACG with a pellets filling set up using standard format size 0 tooling for capsule opening, transport, filling and closing. The machine output was set to 5,000-5,400 cps/hour.

[0138] Capsules tested in automatic capsule filling machine, 3.0 mg/cm.sup.2 polymer or 3.6 mg/cm.sup.2 total solid weight gain feasible to process automatically. Capsule filling operation was smooth, capsules body and caps were easily opened and fit into the machine parts. Yield of 98% could be achieved (only 2% capsules were rejected by machine) on automatic capsule filling machine.

[0139] Dissolution Test

[0140] Method:

[0141] Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

[0142] Detection method: HPLC analysis

[0143] Temperature: 37.5° C.

[0144] Media I: 500 ml 0.1 N HCL for 2 hours

[0145] Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

[0146] Paddle speed: 100 rpm

TABLE-US-00004 TABLE 3 Dissolution Results (n = 12) Example 1 Time Mean Media [min] [% released] SD 0.1N HCL 0 0.0 0.0 0.1N HCL 120 2.8 1.8 pH 6.8 135 27.5 9.4 pH 6.8 150 89.0 10.2 pH 6.8 165 97.0 2.0 pH 6.8 180 95.7 1.5

Example 2 (Comparative)—Enteric Coating of EUDRAGIT® L 30D-55 and EUDRAGIT® NM 30D Combination on Filled and Locked Capsules (Omeprazole Pellets) in Drum Coater

[0147] Encapsulation Parameter

[0148] 590 mg of Omeprazole pellets (5% Omeprazole) were filled into the Kcaps HPMC Size 0 capsules using an automatic Capsule filling equipment AFTLAB. ACG with a pellets filling set up using standard format size 0 tooling for capsule opening, transport, filling and closing. The machine output was set to 5,000-5,400 cps/hour.

[0149] Capsule filling operation was smooth, capsules body and caps were easily opened and fit Into the machine parts. Yield of 99.7% could be achieved (only 0.3% capsules were rejected by machine) on automatic capsule filling machine.

[0150] Enteric Coating on Omeprazole Flied Capsules:

[0151] The EUDRAGIT® polymer(s) were mixed in a suitable sized container. The additional excipients were added into the water while gently stirring. After a suitable post stirring time the excipient suspension was added to the polymer dispersion. The spraying suspension was gently stirred during the coating process. The omeprazole filled capsules were then coated in the locked state utilizing a drum coater.

TABLE-US-00005 TABLE 4 Formulation Example 2- Coating on Omeprazole filled Kcaps ® HPMC Size 0 capsules (Batch size 550 g i.e 833 capsules) Solid Composition Material Composition Percentage EUDRAGIT ® L 30 D-55 2.7 mg/cm.sup.2 75.0% EUDRAGIT ® NM 30D 0.3 mg/cm.sup.2 8.33% Triethyl citrate 20% on ds* 16.67% Demineralized water On demand n/a Solid content 10% w/w Total solid weight gain 3.6 mg/cm.sup.2 *Quantity based on dry polymer substance [%]

TABLE-US-00006 TABLE 5 Process Parameter Example 2 Parameter Value Machine Neocota 5D Batch size [g] 550    Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat pattern pressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.] 50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 35-38 Exhaust air temperature [° C.] 29-30 Product temperature [° C.] 28-29 Spray rate [g/min/kg] 1.36-2.72 Process time [min] 120   

[0152] Dissolution Test

[0153] Method:

[0154] Apparatus: Labindia DS 8000 Paddle Apparatus (USP 11) with sinkers

[0155] Detection method: HPLC analysis

[0156] Temperature: 37.5° C.

[0157] Media I: 500 ml 0.1 N HCL

[0158] Paddle speed: 100 rpm

TABLE-US-00007 TABLE 6 Dissolution Results (n = 12) Example 1 Time Mean Media [min] [% released] SD 0.1N HCL 0 0.0 0.0 0.1N HCL 120 25.8 20.4

[0159] Dissolution testing of Example-2 was only carried out in the 0.1N HCl for 2 hours because Acid release/degradation of Omeprazole observed after 2 hours exposure to 0.1N HCl. At same coating build up enteric polymer coating on filled and locked capsules failed to give acid resistance as compared to coating on Pre-locked capsules followed by filling (Example-1).

Example 3 (Comparative)—Enteric Coating of EUDRAGIT® L 30D-55 and EUDRAGIT® NM 30D Combination on p-Locked Capsules in Drum Coater and Automatic Capsule Filling

[0160] The EUDRAGIT® polymer(s) were mixed in a suitable sized container. The additional excipients were added into the water while gently stirring. After a suitable post stirring time the excipient suspension was added to the polymer dispersion. The spraying suspension was gently stirred during the coating process. The capsules were coated in the pre-locked state utilizing a drum coater.

TABLE-US-00008 TABLE 7 Formulation Example 3- Coating on Kcaps ® HPMC Size 0 capsules (Batch size 90 g i.e. 833 capsules) Solid Composition Material Composition Percentage EUDRAGIT ® L 30 D-55 4.5 mg/cm.sup.2 75.0% EUDRAGIT ® NM 30D 0.5 mg/cm.sup.2 8.33% Triethyl citrate 20% on ds* 16.67% Demineralized water On demand n/a Solid content 10% w/w Total solid weight gain   6 mg/cm.sup.2 *Quantity based on dry polymer substance [%]

TABLE-US-00009 TABLE 8 Process Parameter Example 3 Parameter Value Machine Neocota 5D Batch size [g] 90   Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat pattern pressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.] 50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 32-38 Exhaust air temperature [° C.] 28-32 Product temperature [° C.] 28-30 Spray rate [g/min/kg]  8-16 Process time [min] 375   

[0161] Encapsulation Parameter

[0162] 595 mg of Omeprazole pellets (5% Omeprazole) was filled into the polymer coated pre-locked capsules using an automatic Capsule filling equipment AFTLAB, ACG with a pellets filling set up using standard format size 0 tooling for capsule opening, transport, filling and closing. The machine output was set to 1,000-1,200 cps/hour.

[0163] Capsules tested in automatic capsule filling machine. At 5.0 mg/cm.sup.2 polymer or 6.0 mg/cm.sup.2 total solid weight gain the limitation was the standard tooling which was not able to operate with the pre-locked capsules due to the increased layer thickness. Capsule filling operation was not smooth, capsules body and caps were easily opened but failed to fit into the machine parts due to increase in the coating thickness. Yield of only 67% could be achieved and 33% capsules were rejected by the machine. Due to high rejection rate the filed capsules were not analyzed for dissolution testing.

Example 4 (Inventive)—Enteric Coating of EUDRAGIT® FS 30D and EUDRAGIT® L 30-65 Combination on p-Locked Capsules in Drum Coater and Automatic Capsule Filling

[0164] The EUDRAGIT® polymer(s) were mixed in a suitable sized container. The additional excipients were added Into the water while gently stirring. After a suitable post stirring time the excipient suspension was added to the polymer dispersion. The spraying suspension was gently stirred during the coating process. The capsules were coated in the pre-locked state utilizing a drum coater.

TABLE-US-00010 TABLE 9 Formulation Example 4 - Coating on Kcaps ® HPMC Size 0 capsules (Batch size 90 g i.e. 833 capsules) Solid Composition Material Composition Percentage EUDRAGIT ® FS 300 2.25 mg/cm.sup.2 68.18% EUDRAGIT ® L 30 D-55 0.75 mg/cm.sup.2 22.73% Triethyl citrate 10% on ds* 9.09% Demineralized water On demand n/a Solid content 10% w/w Total solid weight gain  3.3 mg/cm.sup.2 *Quantity based on dry polymer substance [%]

TABLE-US-00011 TABLE 10 Process Parameter Example 4 Parameter Value Machine Neocota 5D Batch size [g] 90   Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat pattern pressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.] 50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 36-38 Exhaust air temperature [° C.] 28-29 Product temperature [° C.] 28-29 Spray rate [g/min/kg] 8   Process time [min] 240   

[0165] Encapsulation Parameter

[0166] 525 mg of Metoprolol pellets (40% Metoprolol) were filled into the polymer coated pre-locked capsules using an automatic Capsule filling equipment AFTLAB, ACG with a pellets filling set up using standard format size 0 tooling for capsule opening, transport, filling and closing. The machine output was set to 5,000-5,400 cps/hour.

[0167] Capsules tested in automatic capsule filling machine, 3.0 mg/cm.sup.2 polymer or 3.3 mg/cm.sup.2 total solid weight gain feasible to process automatically. Capsule filling operation was smooth, capsules body and caps were easily opened and fit into the machine parts. Yield or 97% could be achieved (only 3% capsules were rejected by machine) on automatic capsule filling machine.

[0168] Dissolution Test

[0169] Method:

[0170] Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

[0171] Detection method: HPLC analysis

[0172] Temperature: 37.5° C.

[0173] Media I: 500 ml 0.1 N HCL for 2 hours

[0174] Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

[0175] Media III: 900 ml KH2PO4 pH 7.4 buffer for 2 hours

[0176] Paddle speed: 100 (media1)/100 (media2)/50 (media3)

TABLE-US-00012 TABLE 11 Dissolution Results (n = 12) Example 4 Time Mean Media [min] [% released] SD 0.1N HCL 0 0.00 0.00 0.1N HCL 120 0.18 0.34 pH 6.8 180 14.56 19.77 pH 7.4 195 34.89 20.80 pH 7.4 210 54.54 15.56 pH 7.4 225 71.56 9.94 pH 7.4 240 83.58 7.44 pH 7.4 270 90.44 6.71 pH 7.4 300 91.30 7.84

Example 5 (Comparative)—Enteric Coating of EUDRAGIT® FS 30D and EUDRAGIT® L 30D-55 Combination on Filled and Locked Capsules (Metoprolol Pellets) in Drum Coater

[0177] Encapsulation Parameter

[0178] 517 mg of Metoprolol pellets (40% Metoprolol) were filled Into the Kcaps HPMC Size 0 capsules using an automatic Capsule filling equipment AFTLAB. ACG with a pellets filling set up using standard format size 0 tooling for capsule opening, transport, filling and closing. The machine output was set to 5,000-5,400 cps/hour.

[0179] Capsule filling operation was smooth, capsules body and caps were easily opened and fit Into the machine parts. Yield of 100% could be achieved on automatic capsule filling machine.

[0180] Enteric Coating on Metoprolol Filled Capsules:

[0181] The EUDRAGIT® polymer(s) were mixed in a suitable sized container. The additional excipients were added into the water while gently stirring. After a suitable post stirring time the excipient suspension was added to the polymer dispersion. The spraying suspension was gently stirred during the coating process. The Metoprolol filled capsules were then coated in the locked state utilizing a drum coater.

TABLE-US-00013 TABLE 12 Formulation Example 5- Coaling on Metoprolol filled Kcaps ® HPMC Size 0 capsules (Batch size 550 g i.e 833 capsules) Solid Composition Material Composition Percentage EUDRAGIT ® FS 30D 2.25 mg/cm.sup.2 58.18% EUDRAGIT ® L 30 D-55 0.75 mg/cm.sup.2 22.73% Triethyl citrate 10% on ds* 9.09% Demineralized water On demand n/a Solid content 10% w/w Total solid weight gain  3.3 mg/cm.sup.2 *Quantity based on dry polymer substance [%]

TABLE-US-00014 TABLE 13 Process Parameter Example 5 Parameter Value Machine Neocota 5D Batch size [g] 550    Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomizing pressure [bar] 1.5 Flat pattern pressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.] 50-55 Pan speed [rpm] 11   Inlet air temperature [° C.] 36-38 Exhaust air temperature [° C.] 28-30 Product temperature [° C.] 28-29 Spray rate [g/min/kg] 1.36-2.72 Process time [min] 140   

[0182] Dissolution Test

[0183] Method:

[0184] Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

[0185] Detection method: HPLC analysis

[0186] Temperature: 37.5° C.

[0187] Media I: 500 ml 0.1 N HCL for 2 hours

[0188] Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

[0189] Media III: 900 ml KH2PO4 pH 7.4 buffer for 2 hours

[0190] Paddle speed: 100 (media1)/100 (media2)/50 (media3)

TABLE-US-00015 TABLE 14 Dissolution Results (n = 12) Example 5 Time Mean Media [min] [% released] SD 0.1N HCL 0 0.0 0.0 0.1N HCL 120 27.3 40.6 pH 6.8 180 84.9 16.0

[0191] Dissolution testing of Example-5 was only carried out in the 0.1N HCl for 2 hours and pH 6.8 buffer for 1 hour because complete release of Metoprolol observed in pH 6.8 buffer. At same coating build up enteric polymer coating on filled and locked capsules failed to give acid resistance as compared to coating on Pre-locked capsules followed by filling (Example-4).

Example 6 (Inventive)—Enteric Coating of EUDRAGIT® L 30D-55 and EUDRAGIT® NM 30D Combination on Pre-Locked Capsules Followed by Top Coat of HPMC in Drum Coater and Automatic Capsule Filling

[0192] The EUDRAGIT® polymer(s) were mixed in a suitable sized container. The additional excipients were added into the water while gently stirring. After a suitable post stirring time the excipient suspension was added to the polymer dispersion. The spraying suspension was gently stirred during the coating process. The capsules were coated in the pre-locked state utilizing a drum oater. Top coat: HPMC was dissolved in water under stirring and sprayed on to the coated capsules utilizing a drum coater.

TABLE-US-00016 TABLE 15 Formulation Example 6- Coaling on Kcaps ® HPMC Size 0 capsules (Batch size 500 g i.e. 4595 capsules) Solid Composition Coating Material Composition Percentage Functional coat EUDRAGIT ® L 30 D-55 1.8 mg/cm.sup.2 75.0% EUDRAGIT ® NM 30D 0.2 mg/cm.sup.2 8.33% Triethyl citrate 20% on ds* 16.67% Demineralized water On demand n/a Solid content 10% w/w Total solid weight gain 2.4 mg/cm.sup.2 Top coat HPMC 3cps 0.5 mg/cm.sup.2 100% Demineralized water On demand n/a Solid content 5% w/w Total solid weight gain 0.5 mg/cm.sup.2 *Quantity based on dry polymer substance [%]

TABLE-US-00017 TABLE 16 Process Parameter Example 6 Value Value Functional coat Top coat Parameter (EUDRAGIT ®) (HPMC) Machine Neocota 5D Neocota 5D Batch size [g] 500    559    Nozzle bore [mm] 0.8 0.8 Internal tube diameter [mm] 3.0 3.0 Peristaltic pump Flowtech Flowtech Atomizing pressure [bar] 1.5 1.5 Flat pattern pressure [bar] 1.0 1.0 Room temperature [° C.] 21-24 21-24 Room humidity [% r.h.] 50-55 50-55 Pan speed [rpm] 8   8   Inlet air temperature [° C.] 50-58 38-40 Exhaust air temperature 28-31 29-31 [° C.] Product temperature [° C.] 27-29 28-29 Spray rate [g/min/kg] 4.5-18  6.70-10.7 Process time [min] 105    60  

[0193] Encapsulation Parameter

[0194] 590 mg of Omeprazole pellets (5% Omeprazole) were filled into the polymer coated pre-locked capsules using an automatic Capsule filling equipment AFTLAB, ACG with a pellets filling set up using standard format size 0 tooling for capsule opening, transport, filling and closing. The machine output was set to 5,000-5,400 cps/hour.

[0195] Capsules tested in automatic capsule filling machine, 2.5 (2.0 EUDRAGIT+0.5 HPMC) mg/cm polymer or 2.9 (2.4 EUDRAGIT+0.5 HPMC) mg/cm.sup.2 solid weight gain feasible to process automatically. Capsule filling operation was smooth, capsules body and caps were easily opened and fit into the machine parts. Yield of 95% could be achieved (only 5% capsules were rejected by machine) on automatic capsule filling machine.

[0196] Dissolution Test

[0197] Method:

[0198] Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

[0199] Detection method: HPLC analysis

[0200] Temperature: 37.5° C.

[0201] Media I: 500 ml 0.1 N HCL for 2 hours

[0202] Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

[0203] Paddle speed: 100 rpm

TABLE-US-00018 TABLE 17 Dissolution Results (n = 6) Example 1 Time Mean Media [min] [% released] SD 0.1N HCL 0 0.0 0.0 0.1N HCL 120 1.7 0.6 pH 6.8 135 43.7 10.8 pH 6.8 150 91.6 7.1 pH 6.8 165 94.4 1.4 pH 6.8 180 93.3 1.3

Comparative Example 7—Enteric Coating of Standard EUDRAGIT® L 30D-55 Coating with Glycerol Mono Stearate (GMS) on Pre-Locked Capsules Followed by Top Coat of HPMC in Drum Coater and Automatic Capsule Filling

[0204] GMS emulsion was prepared by adding Polysorbate 80 (33% solution), Triethyl citrate and GMS in hot ater (70-80° C.) under high shear homogenizer for 10 minutes. Prepared GMS emulsion was allowed to cool down at room temperature and then added to EUDRAGIT® polymer dispersion under overhead stirring. The spraying suspension was gently stirred during the coating process. The capsules were coated in the pre-locked state utilizing a drum coater. Top coat: HPMC was dissolved in water under stirring and sprayed on to the coated capsules utilizing a drum coater.

TABLE-US-00019 TABLE 18 Formulation Example 7- Coaling on Kcaps ® HPMC Size 0 capsules (Batch size 90 g i.e. 833 capsules) Solid Composition Coating Material Composition Percentage Functional coat EUDRAGIT ® L   2 mg/cm.sup.2 85.47% 30 D-55 Polysorbate 80 2% on ds* 1.71% (33% solution) Triethyl citrate 10% on ds* 8.55% Glycerol mono stearate 5% on ds* 4.27% Demineralized water On demand n/a Solid content 10% w/w Total solid 2.34 mg/cm.sup.2  weight gain Top coat HPMC 3cps 0.5 mg/cm.sup.2 100% Demineralized water On demand n/a Solid content 5% w/w Total solid 0.5 mg/cm.sup.2 weight gain *Quantity based on dry polymer substance [%]

TABLE-US-00020 TABLE 19 Process Parameter Example 7 Value Value Functional coat Top coat Parameter (EUDRAGIT ®) (HPMC) Machine Neocota 5D Neocota 5D Batch size [g] 90   100    Nozzle bore [mm] 0.8 0.8 Internal tube diameter [mm] 3.0 3.0 Peristaltic pump Flowtech Flowtech Atomizing pressure [bar] 1.5 1.5 Flat pattern pressure [bar] 0.5 0.5 Room temperature [° C.] 21-24 21-24 Room humidity [% r.h.] 50-55 50-55 Pan speed [rpm] 11   11   Inlet air temperature [° C.] 34-36 36-37 Exhaust air temperature 27-31 30-31 [° C.] Product temperature [° C.] 27-29 28-29 Spray rate [g/min/kg]  8.33-16.66  8.33-16.66 Process time [min] 120    30  

[0205] Encapsulation Parameter

[0206] 590 mg of Omeprazole pellets (5% Omeprazole) were filed Into the polymer coated pre-locked capsules using an automatic Capsule filling equipment AFTLAB, ACG with a pellets filling set up using standard format size 0 tooling for capsule opening, transport, filling and closing. The machine output was set to 5,000-5,400 cps/hour.

[0207] Capsules tested in automatic capsule filling machine, 2.5 (2.0 EUDRAGIT+0.5 HPMC) mg/cm.sup.2 polymer or 2.85 (2.35 EUDRAGIT+0.5 HPMC) mg/cm.sup.2 solid weight gain feasible to process automatically. Capsule filling operation was smooth, capsules body and caps were easily opened and fit into the machine parts. Yield of 98.36% could be achieved (only 1.6% capsules were rejected by machine) on automatic capsule filling machine.

[0208] Dissolution Test

[0209] Method:

[0210] Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

[0211] Detection method: HPLC analysis

[0212] Temperature: 37.5° C.

[0213] Media I: 500 ml 0.1 N HCL for 2 hours

[0214] Media II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

[0215] Paddle speed: 100 rpm

TABLE-US-00021 TABLE 20 Dissolution Results (n = 6) Example 1 Time Mean Media [min] [% released] SD 0.1N HCL 0 0.00 0.00 0.1N HCL 120 11.02 3.16 pH 6.8 135 43.63 17.04 pH 6.8 150 86.71 11.45 pH 6.8 165 90.61 14.95 pH 6.8 180 94.22 7.95

Example 8—Determination of Capsule Overlap

[0216] Dimensions and tolerances of different commercially available capsules with respect to mean difference between pre-locked and locked lengths.

TABLE-US-00022 TABLE 21 Hard-shell Capsule Dimensions (1/2) Capsugel Capsugel Capsugel Manufacturer Transparent White Transparent Color #0 Vcaps ® plus #0 Vcaps ® plus #1 Vcaps ® plus Size Un- pre- Final- Un- pre- Final Un- pre- Final Locking stage locked locked Locked locked locked Locked locked locked Locked Length [mm] 29.16 23.65 21.38 29.16 23.76 20.91 26.39 21.19 19.03 SD [mm] 0.19 0.2 0.16 0.17 0.15 0.07 Minimum [mm] 23.25 21 23.43 20.67 20.95 18.9 Maximum 23.95 21.7 23.99 21.31 21.4 19.15 [mm] Overlap length 5.51 2.27 5.4 2.85 5.2 2.16 [mm] Total Overlap 7.78 8.25 7.36 length [mm] Overlap level 71% 100% 65% 100% 71% 100%

TABLE-US-00023 TABLE 22 Hard-shell Capsule Dimensions (2/2) Capsugel ACG ACG Manufacturer Transparent Transparent White Color #3 Vcaps ® plus #0 Naturecaps #0EL Naturecaps Size Un- pre- Final Un- pre- Final Un- pre- Final Locking stage locked locked Locked locked locked Locked locked locked Locked Length [mm] 21.67 17.69 15.74 29.2 23.04 20.92 32 25.17 22.87 SD [mm] 0.16 0.17 0.12 0.16 0.07 0.17 Minimum [mm] 17.39 15.23 22.65 20.68 25.01 22.59 Maximum [mm] 17.94 15.98 23.21 21.22 25.29 23.1 Overlap length 3.98 1.95 6.16 2.12 6.83 2.3 [mm] Total Overlap 5.93 8.28 9.13 [mm] Overlap level 67% 100% 74% 100% 75% 100%

Example 9—Surface Area Calculation and Colon Targeting Coating of Pre-Locked Capsules in Drum Coater

[0217] Since a certain coating layer thickness is required to achieve the desired film functionality, the required amount of coating material depends on the surface area of the substrate. For this reason coating quantities are expressed as mg of total dry substance per cm.sup.2 of substrate surface area.

[0218] Below the equation of pre-locked capsule surface are is described considering the mean difference between the pre-locked state and the accumulated length of the separate capsule halves, body and cap.

[00001]$A_{\frac{1}{2}\mathrm{Sphere}}=2{\left(\frac{d}{2}\right)}^2\pi$$A_{\mathrm{Cylinder},\mathrm{body}}=2\pi \left(\frac{d}{2}\right)\left(h-h_{\mathrm{overlap}}\right)$$A_{\mathrm{Cylinder},\mathrm{cap}}=2\pi \left(\frac{d}{2}\right)h$$A_{\mathrm{Capsule}-\mathrm{segment}}=A_{\frac{1}{2}\mathrm{sphere}}+A_{\mathrm{Cylinder}}$$A_{\mathrm{Pre}-\mathrm{locked}\mathrm{capsule}}=A_{\mathrm{Body}}+A_{\mathrm{Cylinder}}$

[0219] A=Surface Area

[0220] h=Length

[0221] d=Diameter

Calculation Example 9 for the Calculation of the Outer Capsule Surface in the Pre-Locked State

[0222]

TABLE-US-00024 TABLE 23 Vcaps ® Plus Capsule Specifications: Size 00el 00 0el 0 1 1el 2 3 4 Weight Weight [mg] 130 122 107 96 76 81 61 47 38 Tolerance [mg] ±10 ±7 ±7 ±6 ±5 ±5 ±4 ±3 ±3 Length of the capsules halves (body and cap) Body [mm] 22.20 20.22 20.19 18.44 16.61 17.70 15.27 13.59 12.19 Tolerance [mm] ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 Cap [mm] 12.95 11.74 11.68 10.72 9.78 10.49 8.94 8.08 7.21 Tolerance [mm] ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 ±0.46 External diameter Body [mm] 8.18 8.18 7.34 7.34 6.63 6.63 6.07 5.57 5.05 Cap [mm] 8.53 8.53 7.65 7.64 6.91 6.91 6.35 5.82 5.32 Overall length in the final-locked state Length [mm] 25.3 23.30 23.5 21.70 19.40 20.40 18.00 15.90 14.30 Tolerance [mm] ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30

[0223] FIG. 1/1 shows a schematic drawing of the body (left) and the cap (right) of a Vcaps® Plus size 1 hard-shell capsule with the relevant dimensions in mm. The dimensions are used in the calculation example 9 for the calculation of the outer capsule surface in the pre-locked state. The dimensions are:

[0224] Body: length=16.61 mm, cylinder (length of the cylindrical part)=13.29 mm, outer diameter=6.63 mm

[0225] Cap: length=9.78 mm, cylinder (length of the cylindrical part)=6.32 mm, outer diameter=6.91 mm

[00002]$A_{\frac{1}{2}\mathrm{Sphere},\mathrm{Body}}=2{\left(\frac{6.63}{2}\right)}^2\pi =69.05\left[{\mathrm{mm}}^2\right]$$A_{\mathrm{Cylinder},\mathrm{Body}}=2\pi \left(\frac{6.63}{2}\right)\left(13.29-5.2\right)=168.5\left[{\mathrm{mm}}^2\right]$$A_{\frac{1}{2}\mathrm{Sphere},\mathrm{Cap}}=2{\left(\frac{6.91}{2}\right)}^2\pi =75.\left[{\mathrm{mm}}^2\right]$$A_{\mathrm{Cylinder},\mathrm{Cap}}=2\pi \left(\frac{6.91}{2}\right)6.32=137.2\left[{\mathrm{mm}}^2\right]$$A_{\mathrm{Capsule}-\mathrm{body}}=69.05+168,50=237.55\left[{\mathrm{mm}}^2\right]$$A_{\mathrm{Capsule}-\mathrm{cap}}=75.+137.2=212.2\left[{\mathrm{mm}}^2\right]$$A_{\mathrm{Pre}-\mathrm{locked}\mathrm{capsule}}=237.55+212.2=449.75\left[{\mathrm{mm}}^2\right]$

TABLE-US-00025 TABLE 24 Capsuls Surface Area Parameter Body Cap A.sub.1/2 Sphere [mm.sup.2] 69.05 75.00 A .sub.Cylinder [mm.sup.2] 168.50 137.20 A .sub.Segment [mm.sup.2] 237.55 212.20 A .sub.Pre-locked capsule [mm.sup.2] 449.75