CAPSULE TECHNOLOGY Enteric Capsule Drug Delivery Technology – Achieving Protection Without Coating

By: Hassan Benameur, PhD

INTRODUCTION sections of the GI tract for the purpose of protecting the drug from destruction by gastric acid of the stomach (e.g., proton Enteric capsule drug delivery technology (ECDDT) was pump inhibitors), protecting the active from destruction by developed to provide oral delivery with full enteric protection enzymes of the stomach (e.g., peptides, proteins) or protecting and rapid release in the upper gastrointestinal (GI) tract the stomach from an irritant drug (e.g., enteric coated aspirin). 1 without the use of coatings. ECDDT’s intrinsically enteric Enteric protection has historically been imparted to solid properties are attained by incorporating pharmaceutically dosage forms by applying a seal coat followed by coating at approved enteric polymers in the capsule shell using relatively high weight gains (typically ≥ 10%) with pH-sensitive conventional pin-dipping capsule manufacturing processes. By polymer systems using rotary perforated pan coaters or eliminating the preparation and application steps used for fluidized bed equipment. enteric coating, ECDDT can offer accelerated development The development and scale-up steps associated with timelines and reduced program risk. ECDDT can also enable enteric coating add complexity, time, and risk to drug the oral delivery of sensitive molecules, such as nucleotides programs. An assessment by H2 Pharma Consulting cites the and peptides, biological products such as vaccines, and live following areas where ECDDT could reduce the complexity of biotherapeutic products (LBPs), which can degrade at the high enteric dosage form design and processing: 2 temperatures or can be sensitive to aqueous coating solution associated with pan and fluid bed coating processes. The • Simplify selection of enteric formulation composition 5 enteric properties and rapid release of specialized ECDDT o

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capsule shells have been demonstrated to meet pharmacopeia 5 1

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a r 0 o l e g t n e y . s 1 e s h n r t e d r t , ) e e t . x x Drug Development & Delivery June 2015 Vol 15 No 5 FIGURE 2 through the GI tract. Blood samples were taken at pre-dose and then at regular times post-dose over 12 hours, and anterior and posterior images were acquired at dosing and then post-dose over 12 hours. In vivo results (Figure 2) showed that no pellets were released from ECDDT capsules in the stomach and that the capsule quickly opened in the small intestine 30 minutes from gastric emptying to the onset of drug release from the pellet dissolution. Nexium capsules, opened and released their content in the stomach before gastric emptying. The PK profiles of ECDDT capsules and Nexium capsules showed similar discoloration of the medium. esomeprazole release after 2 hours in rates of drug absorption, particularly in After the acid stage, both capsule the acid stage and more than 90% of terms of peak time T max , elimination samples were cut open to observe the release after 30 minutes in the buffer constant k el and half-life t ½ (Figure 3). filled contents. The content of commercial stage. Overall bioavailability of EMT was acid-resistant capsules consisted of a increased using ECDDT capsule brown liquid with EMT pellets partially formulations, with C max and AUC dissolved, demonstrating that a HUMAN BIO-STUDY RESULTS increased by 56% and 32%, significant amount of acid medium had respectively, in comparison to Nexium. migrated inside the capsules, resulting in Esomeprazole is known to show fast EMT degradation. EMT pellets in ECDDT oral absorption (plasma peak = 1 to 3.5 capsules showed minimal discoloration, hours) and a short half-life (1.5 hours). SUMMARY indicating little to no degradation. To evaluate in vivo performance for the ECDDT capsules (n=6) filled with new technology, ECDDT capsules were Enteric capsule drug delivery EMT pellets were also evaluated filled with EMT-layered uncoated pellets technology utilizes a pharmaceutical- according to the EP/USP dissolution test and compared to Nexium capsules 5

o grade cellulosic enteric formulation as an N

for gastro-resistant dosage forms, using (uncoated gelatin capsules containing

5 aqueous dispersion to produce capsule 1

l USP apparatus II (paddle). The test was enteric coated drug-layered o

V shells by conventional capsule performed at 37ºC/100 rpm for 2 hours multiparticulates) in a randomized, open- 5 manufacturing technology pin-dipping. 1

0 at acid stage (pH 1.2) and then 1 hour label, single-dose, and crossover 2 The enteric properties of capsules have e

n at buffer stage (pH 6.8), with sampling pharmacokinetic and gamma- u

J been evaluated in vitro and the results at regular times. The dissolution behavior pharmacoscintigraphy study using y r

e shown to comply with pharmacopeial v i

l of Nexium 20-mg delayed-release healthy volunteers under fasting state. e

D disintegration and dissolution tests

& capsules (n=6) was also evaluated using Radiolabelled (99mTc) pellets were

t

n criteria. It has been demonstrated with e

m the same protocol. For the dissolution added in both ECDDT capsules and p

o both in vitro testing and in vivo by l e

v test, no solubilization of the ECDDT Nexium hard gelatin capsules size 0 in e

D human gamma-pharmacoscintigraphy

g capsules was observed, and each order to detect the location of capsule u r that ECDDT capsules protect EMT from D capsule showed less than 0.2% (LOD) of opening and content release in the gut xx FIGURE 3 BIOGRAPHY

Dr. Hassan Benameur is Senior Director of Pharmaceutical Sciences at Capsugel. He joined Capsugel in 2002 and currently leads the company’s gastric degradation, do not open in the To view this issue and all back issues online, pharmaceutical sciences department. Prior stomach, and provide fast release in the please visit www.drug-dev.com. to joining Capsugel, he held various positions in Pharmaceutical Research & duodenum. Development within Therapeutica, SMB ECDDT represents a new, faster, and Galephar, and Gattefossé. With more REFERENCES easier means for oral delivery of labile than 20 years of expertise in conventional and advanced drug delivery development, entities, such as peptides, nucleotides, Dr. Benameur brings insightful science into live biopharmaceutical products, and 1. Pawar VK, Meher JG, Singh Y, innovative dosage forms and uses drug vaccines. Integrated enteric functionality Chaurasia M, Reddy BS, Chourasia delivery technology to maximize success MK. Targeting of gastrointestinal tract and reduce attrition in product in a capsule dosage form enables new development, from preformulation to possibilities for rapid prototype for amended delivery of manufacturing using a systematic and development and formulation screening, protein/peptide therapeutics: rational approach. Dr. Benameur is a strategies and industrial perspectives. lecturer at several academic and industrial allows rapid testing of in vivo symposia and was presented the performance and minimizes the risk of Int J Pharm. 2014;196:168-183. Academy of Pharmaceutical Science and out-of-specification events during enteric 2. H2 Pharma Consulting, Ltd. Technology, Japan Award in 2005. He is (Maidstone, Kent ME14 5FR, UK). a member of several major scientific performance challenges on associations, including AAPS, APGI manufacturing scale-up and stability 3. Choonara BF, Choonara YE, Kumar BCRG, PSTJ, and CRS and scientific trials. Avoiding the high temperatures P, Bijukumar D, du Toit LC, Pillay VA. academies. He has also authored 40 5

scientific publications and the inventor of o

Review of advanced oral drug N associated with enteric coating 20 patents. Dr. Benameur is a Chemical 5 1

delivery technologies facilitating the application can also enable oral delivery Engineer and earned his PhD in l o V of actives that require enteric protection protection and absorption of protein Pharmaceutical Sciences from the Free 5

University of Belgium. 1 but are sensitive to thermal degradation. and peptide molecules. 0 2

Biotechnology Advances. e ECDDT trials are underway to n u J further evaluate the technology’s range 2014;32:1269-1282. y r e v i and application, including oral live l e D

& biopharmaceutical products, vaccines, t n e and oral peptide products from m p o l e preclinical to Phase III. u v e D

g u r D

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