Commercially Available Enteric Empty Hard Capsules, Production Technology and Application
Abstract
:1. Introduction
2. Enterosolvency of Solid Dosage Forms
3. Enteric Polymers
3.1. pH-Dependent Enteric Polymers
3.2. Gel-Forming Polymers for Enteric Coating
4. Related Excipients Used in the Formulation of the Capsule Shell
5. Brief Description of the Production and Filling of Hard Capsules
6. Patent Research of Empty Enteric Capsules
7. Commercially Hard Capsules Prepared by ECDDT
7.1. ECDDT Prepared from pH-Dependent Polymers
7.1.1. AR Caps® Capsules
7.1.2. EnTRinsicTM Capsules
7.1.3. Vcaps® Enteric Capsules
7.2. ECDDT Prepared from Gel-Forming Polymers
7.2.1. DRcapsTM Capsules
7.2.2. EMBO CAPS® AP Capsules
7.2.3. BioVXR® Capsules
7.2.4. ACGcapsTM HD Capsules
8. Clinical Studies Performed with Enteric Capsules
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Publication 1 | Applicant | Priority | Composition 2 (Capsule; INNER SHELL of the Capsule; Outer Shell of the Capsule)/Technology |
---|---|---|---|
CN115068436 | Jiangsu Zodiac Pharmaceutical Co., Ltd. | 2022-06-23 | Inner shell (HPMC, and carrageenan, gellan gum, agar, and potassium ions); Outer shell (HPMCP, and Tween® 80) |
CN112546016 | Zhejiang Wanli University | 2022-04-22 | Capsule (HPMCP, agar, potassium chloride, and Tween® 80 in ammonium) |
CN114376982 | Guangdong Pharmacology University | 2022-01-18 | Inner shell (chitosan); Outer shell (Eudragit® L 100, and HPMC) |
EP3881834 | Jiangsu Lefan Capsule Co., Ltd. | 2021-09-22 | Capsule (pullulan, carrageenan, glycerol, and SLS) |
CN215875588 | Zhejiang Xinchang Kangping Capsule Co., Ltd. | 2021-08-30 | Capsule (gelated alginate)/Provided with a special positioning lock ring |
CN112569204 | Hubei Humanwell Pharmaceutical Excipients Co., Ltd. | 2021-03-30 | Inner shell (HPMS, HPMC, and pullulan, guar gum, carrageenan, xanthan gum, agar, and emulsifier); Outer shell (HPMCP) |
CN109846852 | Chongqing Hengsheng Pharmaceutical Capsule Co., Ltd. | 2021-02-26 | Capsule (HPMC, potassium chloride, calcium acetate/ carbonate/citrate, sodium alginate) |
WO2022112422 | Capsugel®, France/ Belgium | 2020-11-25 | Inner shell (gelatin, starch, PVA, and HPMC); Outer shell (HPMCAS, HPMCP, CAP) |
CN111467318 | Hubei Humanwell Pharmaceutical Excipients Co., Ltd. | 2020-07-31 | Inner shell (tragacanth, gellan gum, carrageenan, konjac gum, xanthan gum, guar gum, agar, and calcium ions, and emulsifier, and coated with chitin, and sodium carbonate) |
KR102272658 | Suheung Capsule | 2020-05-26 | Capsule (gelatin, and methoxylamide pectin, and buffer, and emulsifier) |
TW201912150 | Qualicaps® | 2019-04-01 | Capsule (HPMC, MC, HPC, and Eudragit® L, Eudragit® NE, Eudragit® NM, Eudragit® FS 30D and HPMCP, HPMCAS, CAP, and PVA, and plasticizer, and surfactant) |
CN109528689 | Jiangsu Zodiac Pharmaceutical Co., Ltd. | 2018-12-24 | Inner shell (carrageenan, sesbania gum, maltitol, potassium chloride, PVAP); Outer shell (PVAP, and surfactant) |
WO2019020134 | Novamed | 2017-07-24 | Capsule (HPMC, CMC, gelatin, and gellan gum, guar gum, tragacanth, agar, alginate) |
CN106902093 | Huaqiao University | 2017-01-24 | Capsule (alginate, and gellan gum, xanthan gum, carragheen, konjac glucomannan, locust bean gum, guar gum, arabic gum, and potassium ions, and HPMC, HPC, CMC, HPS) |
CN106924211 | Qingdao Blue Valley Pharmaceutical | 2017-01-18 | Inner shell (HPMC, and carrageenan); Outer shell (low acyl gellan gum, and calcium chloride, acetic acid, calcium lactate) |
US2021220285 | Capsugel®, Belgium | 2016-07-22 | Capsule (HPMCAS, HPMCP, CAP, PVAP, and HPMC, and ammonia, ethanolamine) |
KR102335455 | Shinetsu Chemical Co., Ltd. | 2016-07-12 | Capsule (HPMCAS, ammonia) |
US9452141 | Dah Feng Capsule Co., Ltd. | 2015-05-01 | Outer shell (gellan gum, pectin, pullulan, HPMC, and potassium chloride) |
CN104434870 | Shaoxing Kangke Capsule Co., Ltd. | 2015-03-25 | Capsule (gelatin, and SLS, and sodium alginate) |
TWI587880 | Dah Feng Capsule Co., Ltd. | 2015-03-24 | Outer shell (gelatin/ poly triglucose, PVA, modified starch, HPMC, and gellan gum, carrageenan, and monovalent/ divalent salt) |
CN104288120 | Shaoxing Kangke Capsule Co., Ltd. | 2014-10-16 | Capsule (HPMC, and pectin, and SLS, Tween® 80, and glycerol, PEG, and sodium alginate, agar, carrageenan) |
CN103919752 | Lou Zhi | 2014-05-07 | Capsule (HPMCP, and PEG, glycerol, castor oil) |
CN103520134 | Songlin Liu | 2013-10-29 | Capsule (HPMCP, and PPG, glycerol, castor oil) |
CN103394093 | Chongqing Hengsheng Medicinal Capsules | 2013-08-11 | Capsule (HPMC, and carrageenan, and potassium chloride) |
CN103394092 | Chongqing Hengsheng Medicinal Capsules | 2013-08-11 | Capsule (HPMC, and gellan gum, and calcium chloride) |
CN103417511 | Chongqing Hengsheng Medicinal Capsules | 2013-08-11 | Capsule (HPMC, and carrageenan, and calcium chloride) |
CN103432096 | Chongqing Hengsheng Medicinal Capsules | 2013-08-11 | Capsule (HPMC, and carrageenan and potassium citrate) |
CN103330695 | Shaoxing Kangke Capsule Co., Ltd. | 2013-06-05 | Capsule (HPMC, and SLS, Tween® 80, glycerol, PEG, and sodium alginate, agar, carrageenan) |
US10172803 | Capsugel®, Belgium | 2013-03-07 | Capsule (HPMC, and calcium stearate, magnesium stearate, carnauba wax, and guar gum, pectin, carrageenan, xanthan gum, locust bean gum, alginate, alginic acid, tamarind gum, glucomannan, agar, curdlan, gellan gum, collagen) |
TWI554290 | Samsung Fine Chemicals | 2012-06-05 | Capsule (HPMC, HPMCP, and ammonia, sodium hydroxide, and potassium hydroxide) |
JP2018058870 | Capsugel®, Belgium | 2012-05-02 | Capsule (Eudragit® L 100, Eudragit® S 100, Eudragit® RS 100, CAP, CAT, HPMCAS, HPMCP, HPMC, HEC, EC, HPC, CMC, MC, and sorbitan monoesters, sorbitan POE esters, glycerol, PEG, castor oil, SLS, TEC, triacetin); Other similar compounds are also listed. |
US2015080479 | Son Jin Ryul, Park Eun Hee | 2012-03-26 | Capsule (HPMCP, and HPMC, and calcium hydroxide, and ammonia, sodium hydroxide, and potassium hydroxide, and TEC, triacetin, PEG, PPG, and surfactants) |
EP3566698 | Capsugel®, Belgium | 2011-11-09 | Capsule (CAP, CAT, HPMCAS, CMEC, PVAP, and monovalent/divalent carbonates and hydroxides) |
KR20120100305 | Samsung Fine Chemicals | 2011-03-03 | Capsule (HPMCP, and HPMC, and calcium hydroxide, and sodium hydroxide, potassium hydroxide, and hydrogenated corn syrup, TEC, triacetin, PEG, PPG) |
EP3354335 | Capsugel®, Belgium | 2010-10-26 | Capsule (CAP, and HPMC, HPC, EC, MC, CMEC, HPMCAS, HPMCP, and sorbitan monoesters and POE esters, glycerol, PEG, glycol, ricin oleate, SLS, TEC, triacetin, and POE-POP-POE triblock polymers); Other similar compounds are also listed. |
US9603933 | Son Jin Ryul, Baek Hyon Ho | 2010-10-21 | Capsule (HPMCP, and HPMC, and ammonia, sodium hydroxide, potassium hydroxide, calcium hydroxide, and SLS, sugar ester) |
US8710105 | Son Jin Ryul, Baek Hyon Ho | 2010-06-11 | Capsule (HPMCP, HPMCAS, HPMC, MC, carrageenan, agar, sodium alginate, gellan gum, pectin, sodium hydroxide, ammonia, potassium hydroxide, calcium hydroxide) |
US8852631 | Capsugel®, Belgium | 2009-09-24 | Capsule (gellan gum, and HPMC) |
WO2011030952 | Samsung Fine Chemicals | 2009-09-11 | Capsule (gellan gum, and HPMCP, and HPMCAS, and HPMC, MC, and neutralizing agent) |
CN101433526 | Shanghai Huiyuan Plant Capsule Co., Ltd. | 2007-11-13 | Outlet shell (HPS, carrageenan, and calcium chloride, sodium carbonate, and CA) |
WO2009062356 | Shanghai Huiyuan Vegetal Capsule Co., Ltd. | 2007-11-13 | Capsule (PVAP acrylic resin, acetyl pullulan, CAP, 1, 2, 4-benzene tricarboxylic acid acetate, HPMCP, HPMC 1,2,4-benzenetricarboxylate, CAS, succinic acid, acetic acid, HPMC, and monovalent and divalent hydroxides and carbonates, and acetylated gellan gum, carrageenan, agar, pectin, sodium alginate, xanthan gum, scutellaria, paulownia gum, locust bean gum, red algae gum, tamarind gum, tara gum, sclerotium glucan, alginate, carbomers) |
US2010113620 | Aston University | 2007-03-29 | Capsule (HPMC, and alginate, and gellan gum, sodium, and potassium ions, and PEG) |
US6752953 | Yung Shin Pharmaceutical Co. | 2004-06-22 | Capsule (cellulose nitrate, CTA, CAP, MC, EC, HPC, HPMC, HPMCP, and Eudragit® L, Eudragit® S, Eudragit® E, Eudragit® RL, Eudragit® RS, and glycerin, PPG, PEG, DEP, DBP, DBS, TEC, acetyl TEC, acetyl TBC, triacyl glycerol, castor oil); Other similar compounds are also listed. |
WO2004012701 | Ajit Singh, Meena Parashuraman | 2002-08-02 | Capsule (gelatin, and methacrylic acid copolymer, CAP, HPMCP, PVAP, and ammonia, sodium carbonate, sodium bicarbonate, sodium hydroxide, and TEC, DBP, DEP, benzyl phenyl formate, sorbitol, PEG) |
US4138013 | Parke, Davis & Co. | 1976-08-27 | Capsule (HPMC, and CAP, gelatin, the copolymer of methacrylic acid, and methacrylic acid ester) |
GB1529901 | Parke, Davis & Co. | 1975-04-17 | Capsule (gelatin and CAP, HPMCP, the copolymer of methacrylic acid with methacrylic acid ester) |
DE2336807 | Parke, Davis & Co. | 1972-07-20 | Capsule (gelatin, and HPMCP with softener) |
GB743014 | Kodak Ltd. | 1952-05-01 | Capsule (ethyl ether CP, CAP, both prepared in situ) |
GB638284 | Parke, Davis & Co. | 1946-03-25 | Capsule (gelatin, and glycerol, and in situ prepared CAP, and sodium carbonate) |
GB610538 | Gelatin Products Corp. | 1945-11-05 | Capsule (gelatin, and glycerol, in situ prepared CAP, and sodium carbonate) |
US2390088 | Gelatin Products Corp. | 1942-09-24 | Capsule (gelatin, and glycerol, CAP, and sodium carbonate) |
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Pharmacopoeia/Abbreviation | European Pharmacopoeia/Ph. Eur. | United States Pharmacopoeia/USP | Japanese Pharmacopoeia/JP | |||
---|---|---|---|---|---|---|
A. Disintegration test | ||||||
Conditions 1 | 1. | 2. | 1. | 2. | 1. | 2. |
Time (min) | 120 | 60 | 60 | MON | 120 | 60 |
Disks | No | Yes | MON | MON | No | Yes |
Limits (units) | 0/6 | 6/6 | 0/6 | MON | 0/6 | 6/6 |
B. Dissolution test | ||||||
Conditions 1 | 1. | 2. | 1. | 2. | 1. | 2. |
Time (min) | 120 | 45/MON | 120 | 45/MON | 120 | MON |
Limits (%) | ≤10 | Q + 5 | ≤10 | Q + 5 | ≤10 | QMON + 5 |
Pharmacopoeia procedure 2 | Method A Continual two-step dissolution | Method A Continual two-step dissolution | If not specified, proceed with both stages of the test separately | |||
Method B Separated two-step dissolution | Method B Separated two-step dissolution |
Commercial Name/Abbreviation 1 | Chemical Name | Solubility at pH Values 2 |
---|---|---|
Eudragit® FS | A copolymer of methyl acrylate, methyl methacrylate, and methacrylic acid in a ratio of 7:3:1 | 7.0 |
Eudragit® S | A copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:2 | 7.0 |
Eudragit® L | A copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:1 | 6.0 |
Eudragit® FL | A mixture of a copolymer of ethyl methacrylate and methyl methacrylate with a copolymer of methacrylic acid and ethyl methacrylate in a ratio of 1:1 | 5.5 |
CAS | Cellulose acetate succinate | 5.8–6.2 |
CAP | Cellulose acetate phthalate | 5.5–6.2 |
CAT | Cellulose trimellitate | 5.2–5.5 |
HPMCAS | Hydroxypropyl methylcellulose acetate succinate | 5.5–6.8 |
HPMCP | Hydroxypropyl methylcellulose phthalate | 5.0–5.5 |
PVAP | Polyvinyl acetate phthalate | 5.0–5.5 |
Size | 000 | 00EL | 00 | 0EL | 0 | 1EL | 1 | 2EL | 2 | 3 | 4 | 5 |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Body length (mm) | 22.2 | 22.2 | 20.2 | 20.2 | 18.4 | 17.7 | 16.6 | 16.7 | 15.3 | 13.6 | 12.2 | 9.3 |
Cap length (mm) | 12.9 | 12.9 | 11.7 | 11.7 | 10.7 | 10.5 | 9.8 | 9.7 | 8.9 | 8.1 | 7.2 | 6.2 |
Capsule length (mm) | 26.1 | 25.3 | 23.3 | 23.1 | 21.7 | 20.4 | 19.4 | 19.3 | 18.0 | 15.9 | 14.3 | 11.1 |
Weight (mg) 1 | 163 | 130 | 118 | 107 | 96 | 81 | 76 | 66 | 61 | 48 | 38 | 28 |
Volume (mL) | 1.37 | 1.02 | 0.91 | 0.78 | 0.68 | 0.54 | 0.50 | 0.41 | 0.37 | 0.30 | 0.25 | 0.13 |
Product Name | Manufacturer/Country of Origin | Composition of Capsule | Pharmacopoeial Acid Resistance |
---|---|---|---|
A. Capsules prepared from pH-dependent polymers | |||
AR Caps® | CapsCanada/Canada | HPMC, HMPCP | No [29] |
EnTRinsicTM | Capsugel®/USA | CAP | Ph. Eur., USP, JP [60] |
VCaps® Enteric | Capsugel®/USA | HPMC, HPMCAS | Ph. Eur., USP, JP [66] |
B. Capsules prepared from gel-forming polymers | |||
DRcapsTM | Capsugel®/France | HPMC, gellan gum | No [29] |
EMBO CAPS® AP | Suhueng Capsule/ Republic of Korea | HPMC, pectin | No [75] |
BioVXR® | BioCaps®/USA | HPMC, gellan gum/pectin 1 | No [75] |
AGCcapsTM HD | ACG/India | HPMC 2 | Not specified |
Clinical Study | Type of Capsule | Specification of Dosage Form | Single Dose/A Total Dose of Capsules | Capsule Content | Clinical Indication | Patient Population | Clinical Success Rate |
---|---|---|---|---|---|---|---|
Walker, E.G., et al., 2022 [93] | DRcapsTM | - | 2/2 | Bitter extract of Humulus lupulus | Regulating Energy Intake (EI) | 19 | EI ↓ 17.54% |
Reid I. et al., 2022 [94] | Vcaps® Enteric | One capsule with 20 mg of API | 1; 2; 3/NA | Zoledronic acid (ZA); ZA as microparticles | Safety in bone resorption | 5 | Positive after one week |
Zain N. et al., 2022 [95] | DRcapsTM | - | 5/5 | Lyophilized bacteria in FMT | rCDI 1 | 7 | 86% |
Varga A. et al., 2021 [52] | Vcaps® Enteric | - | 5–11/NA | Various parts of fecal suspension | rCDI | 28 | 82.14% |
Reigadas E. et al., 2020 [96] | DRcapsTM | Cap-in-Cap system | 4–5/NA | Lyophilized bacteria in FMT | rCDI | 32 | 87.5% |
Leong K. S. W. et al., 2019 [97] | DRcapsTM | Cap-in-Cap system 2 | 14/28 | Frozen bacteria in FMT | Obesity/insulin resistance in adolescent | 80 | NA |
Jiang Z., et al., 2018 [98] | AR CAPS® | - | NA/27 | Lyophilized bacteria in FMT | rCDI | 31 | 84% |
Chehri M. et al., 2018 [99] | DRcapsTM | Cap-in-Cap system | 25 (daily)/75 | Frozen bacteria in FMT | rCDI | 9 | 88.9% |
Halkjær S. et al., 2018 [100] | DRcapsTM | 25 (daily)/ 12 days | Frozen fecal in FMT | Irritable Bowel Syndrome (IBS) | 52 | 36.4 | |
Staley C. et al., 2017 [101] | DRcapsTM | Cap-in-Cap system | 2–4/NA | Lyophilized bacteria in FMT | rCDI | 49 | 88% |
Khana S. et al., 2016 [102] | DRcapsTM | - | 15/30 1–12/NA | Various numbers of bacteria | rCDI | 15 15 | 80% 86.7% |
Hirsch B. et al., 2015 [103] | DRcapsTM | Cap-in-Cap system + gelatin capsule 3 | 6–22/NA | Frozen bacteria in FMT | rCDI | 19 | 89% |
Youngster I. et al., 2014 [76] | DRcapsTM | Cap-in-Cap system | NA/30 | Frozen bacteria in FMT | rCDI | 20 | 90% |
Jones M. et al., 2012 [104] | DRcapsTM | - | 2 (daily)/126 | Lyophilized bacteria Lactobacillus reuteri NCIMB 30242 | Hypercholesterolemia | 131 | LDL-C 4 ↓ 11.64% |
Jones M. et al., 2012 [105] | DRcapsTM | - | 2 (daily)/126 | Lyophilized bacteria Lactobacillus reuteri | Clinical safety of Lactobacillus reuteri | 131 | Positive; Not quantified |
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Franc, A.; Vetchý, D.; Fülöpová, N. Commercially Available Enteric Empty Hard Capsules, Production Technology and Application. Pharmaceuticals 2022, 15, 1398. https://doi.org/10.3390/ph15111398
Franc A, Vetchý D, Fülöpová N. Commercially Available Enteric Empty Hard Capsules, Production Technology and Application. Pharmaceuticals. 2022; 15(11):1398. https://doi.org/10.3390/ph15111398
Chicago/Turabian StyleFranc, Aleš, David Vetchý, and Nicole Fülöpová. 2022. "Commercially Available Enteric Empty Hard Capsules, Production Technology and Application" Pharmaceuticals 15, no. 11: 1398. https://doi.org/10.3390/ph15111398
APA StyleFranc, A., Vetchý, D., & Fülöpová, N. (2022). Commercially Available Enteric Empty Hard Capsules, Production Technology and Application. Pharmaceuticals, 15(11), 1398. https://doi.org/10.3390/ph15111398