PROCESS FOR PREPARING FILLED HARD-SHELL CAPSULES WITH CELLULOSE OR STARCH-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 in a pre-locked state or a final-locked state. The material of the body and cap contains an ethyl-, methyl-, or propyl-ether of cellulose, starch, or pullulan. The hard-shell capsule is coated with a coating layer, containing one or more anionic cellulose(s), ethyl cellulose, and/or one or more starches comprising at least 35% by weight of amylose, 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. A process for preparing a polymer coated hard-shell capsule, filled with a fill comprising a biologically active ingredient the process comprising, providing the polymer coated hard-shell capsule comprising a body and a cap, in a pre-locked state to a capsule filling machine. separating the body and the cap, filling the body with the fill comprising a biologically active ingredient, and rejoining the body and the cap in a final-locked state: wherein in a closed state the cap overlaps the body either in a pre-locked state or in a final-locked state, wherein a material of the body and the cap comprises an ethyl-, me or propyl-ether of cellulose, starch, or pullulan, wherein the polymer coated hard-shell capsule comprises a coating layer that covers the polymer coated hard-shell capsule in the pre-locked state, wherein the coating layer comprises one or more anionic cellulose(s), ethyl cellulose, and/or one or more starches comprising at least 35% by weight of amylose, wherein the coating layer is present in an amount of about 1 to 5.8 mg/cm.sup.2, and wherein a dried film with a thickness of 250 μm, corresponding to a composition of the coating layer, shows an elongation at break of about 15 to 500%.

2. The process according to claim 1, wherein the one or more anionic cellulose(s) are selected from the group consisting of carboxymethyl ethyl cellulose, a salt of carboxymethyl ethyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, and a mixture thereof.

3. The process according to claim 1, wherein the one or more starches comprising at least 35% by weight of amylose is selected from corn starch, maize starch, pre-gelled starch, acetylated starch, and a combination thereof.

4. The process according to claim 1, wherein the one or more starches comprising at least 35% by weight of amylose comprises 40 to 80% by weight of amylose.

5. The process according to claim 1, wherein the one or more anionic cellulose(s), the ethyl cellulose, and/or the one or more starches comprising at least 35% by weight of amylose have glass transition temperatures T.sub.gm of 130° C. or less.

6. The process according to claim 1, wherein the material of the body and the cap comprises hydroxypropyl cellulose.

7. The process according to claim 1, wherein the coating layer comprises 10 to 100% by weight of the one or more anionic cellulose(s), the ethyl cellulose, and/or the one or more starches comprising at least 35% by weight of amylose, and 90 to 0% by weight of pharmaceutical or nutraceutical excipients.

8. The process according to claim 7, wherein the pharmaceutical or nutraceutical excipients comprise one or more plasticizers and/or one or more detacking agents.

9. The process according to claim 8, wherein the one or more plasticizers is/are selected from the group consisting of an alkyl citrate, a glycerol ester, an alkyl phthalate, an alkyl sebacate, a sucrose ester, a sorbitan ester, a glycerol, a propylene glycol, and a polyethylene glycol.

10. The process according to claim 8, wherein the one or more detacking agents is/are selected from the croup consisting of Ca-stearate, Mg-stearate, glycerol monostearate, and talc.

11. The process according to claim 1, wherein the coating layer comprises an emulsifier.

12. The process according to claim 1, wherein the coating layer comprises polysorbate 80.

13 The process according to claim 1, wherein the capsule filling machine is operated at a speed with an output of 1,000 or more filled and finally closed capsules per hour.

14. A hard-shell capsule, obtained by the process according to claim 1.

Description

Example 1—Determination of Capsule Overlap

[0091] Dimensions and tolerances of different commercially available capsules with respect to mean difference between pre-locked and locked lengths.

TABLE-US-00001 TABLE 1 Hard Shell Capsule Dimensions (1/2) Manufacturer Capsugel Capsugel Capsugel Color Transparent White Transparent Size #0 Vcaps ® plus #0 Vcaps ® plus #1 Vcaps ® plus Locking stage Un- pre- Final- Un- pre- Final Un- pre- Final 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 [mm] 23.95 21.7 23.99 21.31 21.4 19.15 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-00002 TABLE 2 Hard Shell Capsule Dimensions (2/2) Manufacturer Capsugel ACG ACG Color Transparent Transparent White Size #3 Vcaps ® plus #0 Naturecaps #0EL Naturecaps Locking stage Un- pre- Final Un- pre- Final Un- pre- Final 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 2—Surface Area Calculation and Colon Targeting Coating of Pre-Locked Capsules in Drum Coater

[0092] 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. 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{Spher}e}=2{\left(\frac{d}{2}\right)}^2\pi$$A_{\mathrm{Cylinder},\mathrm{body}}=2\pi \left(\frac{d}{2}\right)\left(h-h_{o\nu \mathrm{erlap}}\right)$$A_{\mathrm{Cylinder},\mathrm{cap}}=2\pi \left(\frac{d}{2}\right)h$$A_{\mathrm{Capsule}\text{-}segment}=A_{\frac{1}{2}\mathrm{Spher}e}+A_{\mathrm{Cylinder}}$$A_{\mathrm{Pre}\text{-}\mathrm{locked}\mathrm{capsule}}=A_{\mathrm{Body}}+A_{\mathrm{Cylinder}}$$A=\mathrm{Surface}\mathrm{Area}$$h=\mathrm{Length}$$d=\mathrm{Diameter}$

Calculation Example 2 for the Calculation of the Outer Capsule Surface in the Pre-Locked State

[0093]

TABLE-US-00003 TABLE 3 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

[0094] 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:

[0095] Body: length=16.61 mm, cylinder (length of the cylindrical part)=13.29 mm, outer diameter=6.63 mm

[0096] 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]$$A_{\mathrm{cylinder},\mathrm{Body}}=2\pi \left(\frac{6.63}{2}\right)\left(13.29-5.2\right)=16855\left[{\mathrm{mm}}^2\right]$$A_{\frac{1}{2}\mathrm{Sphere},\mathrm{Cap}}=2{\left(\frac{6.91}{2}\right)}^2\pi =75.00\left[{\mathrm{mm}}^2\right]$$A_{\mathrm{Cylinder},\mathrm{Cap}}=2\pi \left(\frac{6.91}{2}\right)6.32=137.20\left[{\mathrm{mm}}^2\right]$$A_{\mathrm{Capsule}\text{-}\mathrm{body}}=69.05+168.50=237.55\left[{\mathrm{mm}}^2\right]$$A_{\mathrm{Capsule}\text{-}\mathrm{cap}}=75.00+137.20=212.20\left[{\mathrm{mm}}^2\right]$$A_{\mathrm{Pre}\text{-}\mathrm{locked}\mathrm{capsule}}=237.55+212.20=449.75\left[{\mathrm{mm}}^2\right]$

TABLE-US-00004 TABLE 4 Capsule 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

Example 3 (Inventive)—Coating of Pre-Locked Empty Capsules with Anionic Cellulose Polymer in a Drum Coater, Followed by Capsule Filling Using an Automatic Capsule Filling Machine

[0097] HPMCAS (AQOAT® AS LF) polymer was dissolved under stirring for about 30 minutes in a solvent mixture of Ethanol and water. Triethyl citrate was added to the mixture and stirred for another 15 minutes. This solution was used to coat the empty Kcaps® HPMC hard capsules (size #0) in a pre-locked state, using a drum coater (Neocota 5D).

TABLE-US-00005 TABLE 5 Formulation Example 3—Coating on Kcaps ® HPMC Size 0 capsules (Batch size 90 g i.e. 833 capsules) Solid Composition Material Composition Percentage HPMCAS (AQOAT ® AS LF) 2.0 mg/cm.sup.2 76.9% Triethyl citrate 30% on ds* 23.1% Ethanol: Water (80:20) q.s. to 5% w/w solids Solid content 5% w/w Total solid weight gain 2.60 mg/cm.sup.2 *Quantity based on dry polymer substance [%]

TABLE-US-00006 TABLE 6 Process Parameters for Example 3 Parameter Value Machine Neocota 5D Batch size [g] 90 Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0 Peristaltic pump Flowtrietec Atomizing pressure [bar] 1.5 Flat pattern pressure [bar] 0.5 Room temperature [° C.] 20-25 Room humidity [% r.h.] 50-60 Pan speed [rpm] 11 Product temperature [° C.] 30-38 Spray rate [g/min/kg] 11-22

Encapsulation Parameters/Observations

[0098] 568 mg of immediate release metoprolol pellets (40% active) were filled into the polymer coated pre-locked capsules using automatic capsule filling machine 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.

[0099] Capsules filled in the automatic capsule filling machine, were coated with 2.0 mg/cm.sup.2 polymer weight gain corresponding with 2.6 mg/cm.sup.2 total solid weight gain.

Process Observations

[0100] Capsule filling operation was smooth, capsules body and caps were easily opened and fit well into the machine parts. Yield of 96.8% could be achieved (3.2% capsules were rejected by the machine) on automatic capsule filling machine.

Dissolution Test

Method

[0101] Apparatus: Labindia DS 8000 Paddle Apparatus (USP II) with sinkers

[0102] Detection method: HPLC analysis

[0103] Temperature: 37.5° C.

[0104] Media I: 500 ml 0.1 N HCL for 2 hours

[0105] Media II: 500 ml KH2PO4 pH 6.8 buffer for 1 hour

[0106] Paddle speed: 50 rpm

TABLE-US-00007 TABLE 7 Dissolution Results (n = 6) Example 3 Time Mean Standard Media [min] [% released] Deviation 0.1N HCL 0 0.0 0.0 0.1N HCL 120 0.1 0.2 pH6.8 135 85.2 5.2 pH6.8 150 93.5 0.5 pH6.8 165 93.9 0.4 pH6.8 180 93.9 0.5

Film Preparation and Testing

[0107] HPMCAS (AQOAT® AS LF) polymer and triethyl citrate (30% based on dry polymer substance) were dissolved under stirring for about 24 hours in a solvent mixture of Ethanol and water (80:20) (9.0 g solid content, solid composition percentage ration HPMCAS to triethyl citrate [76.9% to 23.1%]). The polymer solution was poured onto a Polytetrafluoroethylen covered glass plate and dried for 4 days at 40° C. After drying the film was conditioned for 16 hours at 23° C. and 50% relative humidity. The resulting film thickness was approx. 250 μm. Elongation at break was determined according to DIN EN ISO 527-3:2019-02. An elongation at break value of 22.5% was obtained.

Conclusion

[0108] The film flexibility of the coating layer composition was sufficient to allow smooth capsule filling using the automatic capsule filling machine without damage of the capsule coating layer meeting the requirements of the US pharmacopeia (USP42-NF37) according to monograph <711>Dissolution of delayed release dosage forms acceptance table 3 and 4.

Example 4 (Comparative)—Coating of Pre-Locked Empty Capsules with a Combination of Anionic Cellulose Polymer & Ethyl Cellulose in a Drum Coater, Followed by Capsule Filling Using Automatic Capsule Filling Machine

[0109] HPMCAS (AQOAT® AS LF) and Ethyl cellulose N7 were dissolved under stirring for about 30 minutes in a solvent mixture of Ethanol and water. Triethyl citrate was added to the mixture and stirred for another 15 minutes. This solution was used to coat the empty Kcaps® HPMC hard capsules (size #0) in a pre-locked state, using a drum coater (Neocota 5D).

TABLE-US-00008 TABLE 8 Formulation Example 4—Coating on Kcaps ® HPMC Size 0 capsules (Batch size 90 g i.e. 833 capsules) Solid Composition Material Composition Percentage HPMCAS (AQOAT ® AS LF) 1.0 mg/cm.sup.2 38.46% Ethyl cellulose N7 1.0 mg/cm.sup.2 38.46% Triethyl citrate 30% on ds* 23.07% Ethanol: Water (80:20) q.s. to 7% w/w solids n/a** Solid content 7% w/w n/a** Total solid weight gain 2.60 mg/cm.sup.2 n/a** *Quantity based on dry polymer substance [%] **not applicable

TABLE-US-00009 TABLE 9 Process Parameters for Example 4 Parameter Value Machine Neocota 5D Batch size [g] 90 Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0 Peristaltic pump Flowtec Atomizing pressure [bar] 1.5 Flat pattern pressure [bar] 0.5 Room temperature [° C.] 21-24 Room humidity [% r.h.] 50-60 Pan speed [rpm] 11 Product temperature [° C.] 29-33 Spray rate [g/min/kg] 11-19

Encapsulation Parameters/Observations

[0110] 568 mg of immediate release metoprolol pellets (40% active) were filled into the polymer coated pre-locked capsules using automatic capsule filling machine 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.

[0111] Capsules filled in the automatic capsule filling machine, were coated with 2.0 mg/cm.sup.2 polymer weight gain corresponding with 2.6 mg/cm.sup.2 solid weight gain.

Process Observations

[0112] Sliding issues from the magazine, some capsules could not be filled into the die cavities.

[0113] For some capsules, cap and body could not be separated.

[0114] Denting on the capsule body was also observed in rejected capsules

[0115] Low yield of 65.2% could be achieved (34.8% capsules were rejected by the machine)

Film Preparation and Testing

[0116] HPMCAS (AQOAT® AS LF), Ethyl cellulose N7 polymer (1:1) and triethyl citrate (30% based on dry polymer substance) were dissolved under stirring for about 24 hours in a solvent mixture of Ethanol and water (80:20) (9.0 g solid content, solid composition percentage HPMCAS:Ethyl cellulose:triethyl citrate [38.46%:38.46%:23.07%]). The polymer solution was poured onto a Polytetrafluoroethylen covered glass plate and dried for 4 days at 40° C. After drying the film was conditioned for 16 hours at 23° C. and 50% relative humidity. The resulting film thickness was approx. 250 μm. Elongation at break was determined according to DIN EN ISO 527-3:2019-02. An elongation at break value of 3.1% was obtained.

Conclusion

[0117] The poor film flexibility of the coating layer composition resulted in poor performance of the coated capsules on the automatic capsule filling machine with high rejection rate and damage of capsules Due to the high rejection rate and observed damages it is expected that the capsules do not fulfill the requirements of the US pharmacopeia (USP42-NF37) according to monograph <711> Dissolution of delayed release dosage forms acceptance table 3 and 4.

Example 5 (Comparative)—Coating of Pre-Locked Empty Capsules with Anionic Cellulose Polymer Without a Plasticizer in a Drum Coater, Followed by Capsule Filling using Automatic Capsule Filling Machine

[0118] HPMCAS (AQOAT® AS LF) polymer was dissolved under stirring for about 45 minutes in a solvent mixture of Ethanol and water. This solution was used to coat the empty capsules in a pre-locked state, using a drum coater Neocota 5D.

TABLE-US-00010 TABLE 10 Formulation Example 5—Coating on Kcaps ® HPMC Size 0 capsules (Batch size 90 g i.e. 833 capsules) Material Composition % solids Composition HPMCAS (AQOAT ® AS LF) 2.0 mg/cm.sup.2 100% Ethanol: Water (80:20) q.s. to 7% w/w solids Solid content 7% w/w Total solid weight gain 2.0 mg/cm.sup.2

TABLE-US-00011 TABLE 11 Process Parameters for Example 5 Parameter Value Machine Neocota 5D Batch size [g] 90 Nozzle bore [mm] 0.8 Internal tube diameter [mm] 3.0 Peristaltic pump Flowtrietec Atomizing pressure [bar] 1.5 Flat pattern pressure [bar] 0.5 Room temperature [° C.] 20-25 Room humidity [% r.h.] 50-60 Pan speed [rpm] 11 Product temperature [° C.] 27-29 Spray rate [g/min/kg] 11-22

Process Observations

[0119] The surface of coated capsules was not smooth, indicative of uneven film formation. Capsule surface did not show any sign of crack or film damage when capsules were pressed.

Preparation of Blend for Capsule Filling

[0120] The dye was co-sifted thru 100 mesh with lactose in ˜1:1 ratio. The blend was mixed in a blender with lactose granules in multiple steps using geometric mixing method. The final blend was unloaded and used for capsule filling.

TABLE-US-00012 TABLE 12 Blend formulation for capsule filling (Example 5) Material % w/w Composition HydroxyNaphthol Blue  1% Lactose granules 99%

Encapsulation Parameters/Observations

[0121] A. Automatic capsule filling machine AFTLAB (ACG) was used with standard format size 0 tooling. The machine output was set to 5,000-5,400 cps/hour. Capsule filling operation was smooth, capsules body and caps were easily opened and fit well into the machine parts. About 250 mg blend was filled into each polymer coated capsule.

[0122] B. For comparison about 250 mg blend was filled into each polymer coated pre-locked capsule manually.

Dye Test

[0123] Method according to USP 42 manograph <701>: Six filled capsules were subjected to the disintegration test using 600 mL of 0.1N HCl for two hours, without sinkers according to European Pharmacopeia, chapter 2.9.1. Any change in color/appearance was noted. Following are the observations;

[0124] A. Within first hour of exposure, four out of six capsules show substantial leakage with appearance of specks in all. Within two hours, substantial leakage was observed followed by disintegration of capsules indicating failure of protection.

[0125] B. Some small specks of purple color observed within first hour, indicative of minor penetration of HCl in capsules. Within two hours, substantial leakage was observed followed by disintegration of capsules.

Film Preparation and Testing

[0126] HPMCAS (AQOAT® AS LF) was dissolved under stirring for about 24 hours in a solvent mixture of Ethanol and water (80:20) (9.0 g solid content, solid composition percentage AQOAT®AS LF was 100%). The polymer solution was poured onto a Polytetrafluoroethylen covered glass plate and dried for 4 days at 40° C. After drying the film was conditioned for 16 hours at 23° C. and 50% relative humidity. The resulting film thickness was approx. 250 μm. Elongation at break was determined according to DIN EN ISO 527-3:2019-02. An elongation at break value of 3.2% was obtained.

Conclusion

[0127] The poor film flexibility of the coating layer composition resulted in coating layer film damage using the automatic capsule filling machine resulting in high failure rate of acid protection. Due to the negative disintegration results it is expected that the capsules do not fulfill the requirements of the US pharmacopeia (USP42-NF37) according to monograph <711> Dissolution of delayed release dosage forms acceptance table 3 and 4.