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As appeared in Tablets & Capsules January 2015 www.tabletscapsules.com

capsules and capsule fillingEncapsulation innovation: The new andnovel in hard and soft capsules

Matthew KnoppEditor

Judged by the number of products on the market, tablets winhands down over capsules. But capsules offer more versatilityin delivering drugs and dietary supplements. Here’s a glimpse atsome of what’s new.

o one expects capsules to overtake tablets as thepreferred pharmaceutical dosage form. Nonetheless, “thecapsule market is increasing by 4 to 5 percent per year inunits, while the average market in units of pharmaceuticalproducts in general is growing by 3 to 4 percent,” saidMartin Opitz, a senior market expert at Robert BoschPackaging Technology, Waiblingen, Germany.

“At present, the ratio of capsules to tablets in theworld is 1-to-5.5, capsules-to-tablets, and it’s always aquestion of where the trend is going. If it’s going morethe capsule way, that doesn’t mean we’ll get close to 1-to-1, but it might become 1-to-4.”

Opitz cited expiring patents as the main driver for thegrowth in capsules versus the market overall: As formerblockbusters have lost patent protection, production ofgeneric versions has soared. He estimated that thenumber of capsules used for making omeprazole wentfrom 1 billion annually to 10 billion after the innovator’sproduct came off patent. “There is a huge boost involume when they become generic,” he said. “Two-thirdsof capsule volume is going to generics and OTCs.”

That’s why it’s important to capture an innovator’sattention at the R&D stage, he said: Whatever process,product, or technology the innovators select, the genericmanufacturers will likely also adopt. That locks in futurerevenue from the follow-on manufacturers and “allows ourcapsule filling technology to stay long term,” Opitz said.

That long-term relationship and the promise of biggervolumes also appeal to suppliers of capsule shells, such asCapsugel, Greenwood, SC, as well as CDMOs thatformulate and manufacture softgels, such as Patheon,Durham, NC, and Catalent, Somerset, NJ.

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Branching outTo capture that business, suppliers have been

broadening the application of their products andexpanding their offerings. Capsugel, one the largestsuppliers of capsule shells, has added a number oftechnologies to its portfolio under its Dosage FormSolutions (DFS) business unit. In March 2013, it acquiredScotland’s Encap Drug Delivery, giving it more expertisein liquid-filled lipid formulations and a commercialmanufacturing facility. In October 2013, it acquired BendResearch, Bend, OR, which specializes in enhancingbioavailablity and modifying API release using spray-dried dispersions and hot-melt extrusions.

Still, capsules remain Capsugel’s foundation, a factunderscored by the posters it presented at the annualmeeting of the American Association of PharmaceuticalScientists (AAPS) in San Diego, CA, in November. “Wewant to educate people about the advances that aretaking place in capsule technology,” said Missy Lowery,Capsugel’s senior manager of marketing for the Americas.“It’s an extremely flexible dosage form.”

One example is a multi-compartment capsule underdevelopment at one of the company’s R&D sites. In thisvariation of the capsule-in-capsule approach, one or morecapsule caps are inserted into a standard capsule, enablinga single capsule to carry two or more formulations [1]. TheAAPS poster presented experimental case studies thatdemonstrated the possible applications and concluded thatthe technique can be applied to combinations of all typesof hard capsule polymers. “It’s something that we havebeen developing just to see the feasibility,” said DomiqueCadé, Capsugel’s director of polymer science. “It’s part ofour push to offer our ideas to the pharmaceutical industry,to see where it fits, the right application.”

Another poster summarized a study on theperformance of Capsugel’s acid-resistant DRcaps capsulesafter being band-sealed with an ammonia-neutralizedcellulosic formula [2]. In vitro tests showed the bandprevented the body and cap from separating until theyreached a higher pH environment. Later this year,Capsugel will begin commercial trials of the bandingtechnology among its pharmaceutical and dietarysupplement customers.

Getting capsules to the target destination was criticalfor Dr. Elizabeth L. Hohmann and her colleagues atMassachusetts General Hospital, Boston, MA. Their workinvolved transplanting donated fecal matter to the largeintestines of patients suffering from clostridium difficilecolitis [3]. The effectiveness of the transplantations waswell established, but the first methods used—colonoscopies and intubation—were fraught withproblems. Capsugel’s acid-resistant HPMC capsulesprovided a solution. The HPMC polymer held up to theliquid fill, and the capsules’ acid resistance ensuredpassage through the stomach intact, opening only whenthey reached the large intestine. Double encapsulation—a size 00 within a size 0—and deep-freezing kept thecapsules intact until they were dispensed (15 capsules aday over 2 days).

“Most people just close their eyes and take it rightdown,” Hohmann said. “[The appearance] is really just anaesthetic concern because they’re totally odorless andtasteless. And because they’re frozen, they frost over alittle bit when you get them in the air. So it doesn’tmatter that much.” Eighteen of 20 patients were treatedsuccessfully using the capsules, and since the initialresults were announced in October, Hohmann and hercolleagues have treated 30 more patients with similarsuccess.

Capsugel conducted several experimental case studies of its multi-compartmentcapsule to demonstrate possible applications [1].

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Acid-resistant HPMC capsules give physicians a better method of transplantingfecal matter to the large intestine [3].

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Another study presented at the AAPS meetingcompared how hard capsules made from differentpolymers performed in drug delivery via the vagina [4], amethod that, like ocular delivery, shows promise inovercoming the blood-brain barrier. The study’s authorsstated that many new products that employ hard capsulesfor vaginal applications failed to account for the capsule’snature or functionality. Their tests, conducted using atexture analyzer, showed that pullulan capsules—Capsugel’s Plantcaps—provided rapid content releasethrough quick disintegration. The pullulan also helpedkeep the capsule in place through strong bio-adhesion.

Micro-dosingCapsules also have applications in pulmonary delivery,

typically in dry powder inhalers (DPIs). Capsugelpresented data about how different hard capsulesperformed in different DPIs [5], and Qualicaps, a capsulesupplier based in Whitsett, NC, offered posters thatevaluated how capsule composition (HPMC versusgelatin) and temperature affected puncture performance[6-8]. [Editor’s note: For more information about nasal andpulmonary delivery, see Tablets & Capsules’ sister magazineInhalation: www.inhalationmag.com.]

Whatever capsules are used in DPIs, it’s critical thatthey contain the right powder dose. Until recently, thatusually meant filling them using a dosator-style capsulefilling machine, because tamping-style machines were notreally suitable. Bosch, known best for tamping machines,will begin offering dosator-style machines this year. It hasalso developed a new technology, called a vacuum dosingwheel. It dispenses as little as 1 milligram of powder at astandard deviation of ±2 percent and can fill capsuleswith as much as 200 milligrams.

It can also micro-dose other types of powders. “We seemore and more applications in dosing pure APIs and indosing very small formulations,” Opitz said. “For [fills] upto 100 milligrams, it can be very accurate, this wheeltechnology. It’s completely different from tamping pins,”he said, noting that immediate-release formulations arean appropriate application. “If you have a good solubleAPI, why should you go the way of formulation, whereyou have to test the interactions between the excipients,API, and capsule shell? Why don’t you fill the APIdirectly into the capsule? More and more, we’re seeingrequests from formulators who are thinking about puttingjust API in the final product.”

Originally, filling capsules with neat API was a methodto accelerate clinical trials, and one of the first micro-dosing systems to take hold was Xcelodose, a technologythat Capsugel acquired in 2005. Another micro-dosingsystem, Quantos, was introduced in 2008 by Mettler-Toledo, Columbus, OH. Opitz, who worked at Capsugeluntil 2013, called the Xcelodose “fantastic,” because ithelps bring products to market quickly. But the dosingwheel is a better fit for scale-up and large-scaleproduction, he said. “We improved the system so much inthe last year, 2014, and it can handle a big range of

different kinds of APIs or formulations in small amounts.The wheel allows you to adjust quantities, so during drugdevelopment, you can play around with differentquantities by adjusting it.”

Softgel scienceSoftgel capsules offer formulators additional flexibility.

In October 2012, Patheon acquired Banner Pharmacaps,the world’s second-largest pharmaceutical businessdedicated to softgel formulations. “Banner gave us addedvalue,” said Anil Kane, executive director and global headof formulation sciences at Patheon. “We now can provideour clients with a softgel dosage form for delivery ofimmediate-release, controlled-release, as well as areas forpediatrics, geriatrics, and other special types of delivery,such as enteric-release softgels.” Technologies includeEnteriCare enteric-release softgels, Versatrol controlled-release softgels, Solvatrol softgels for enhanced solubility,LiquiSoft pediatric softgels, Chewels chewable forms, andtwist-offs. The twist-off capsules can hold a large liquiddose, which is squeezed into the mouth. They help delivermedicine to pediatric and geriatric patients, as well asothers who have difficulty swallowing tablets or capsules.

Kane said the special equipment, excipients, andexpertise that softgels require aren’t an issue forcustomers. “They prefer to outsource this to specializedgroups. I don’t think it’s the best use of a firm’s in-houseskill sets to develop a small number of products in aspecialized dosage like a softgel. I think it’s advantageousto outsource to a specialist rather than trainingindividuals and investing in this in-house.”

It may even be faster to use a softgel instead of a liquid-filled hard capsule to get new products to market. “We cando a very small, benchtop, proof-of-concept in softgels,”Kane said. “We can also take softgels from phase 1 throughto later phases of development and on to commercial muchfaster because the vehicle is the same,” he said. “So thescalability is much faster, and the output can be muchhigher than the two-piece liquid-filled hardshell, whichneeds additional steps, such as banding, sealing, anddrying. We see a lot more benefits with the softgel.”

Bosch’s vacuum dosing wheel dispenses as little as 1 milligram of powder at astandard deviation of ±2 percent.

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In fact, liquid-filled hard capsules have not been aspopular as forecast, Opitz said. “It’s a fantastic technologyfor insoluble APIs, and some years ago there was a bighope that a lot of products would come out, and there aresome for sure. But it’s not the boom that we expected atBosch. We haven’t sold that many liquid filling machineslinked to the SMEDDS and SEDDS systems.”

Another of Patheon’s technologies, Softlet gelatinenrobing, offers an alternative to over-encapsulation, thestandard method of blinding clinical trial materials.

“Sometimes the tablet is large and it’s a challenge to fitinto a blinded hard capsule,” Kane said. “Actually, we areseeing more of that: fixed-dose combinations gettinglarger and larger, and it’s a challenge to fit them in ablinded capsule, so a Softlet enrobing approach can help.It’s all based on engineering, devising the tooling.” Odd-shaped tablets, multiple tablets, and powder- or pellet-filled capsules can also be enrobed to blind clinical trialmaterials. “There is no one solution that solves allproblems. Our approach is to provide the fastest andmost cost-effective approach, whether it’s a two-pieceshell or softgel form.”

Softgels can also help formulators overcome thedifficulty of delivering biopharmaceuticals via the oralroute. “No major breakthrough in the effective oraldelivery of peptides/proteins has been accomplished,”said Shinji Yamashita of Setsunan University, Osaka,Japan [9]. At the same time, there is a trend in drugdevelopment toward bio-molecules over small-moleculecompounds, he said, and that has increased the demandfor oral delivery of biologics, especially of therapeuticpeptides and proteins.

Catalent, for one, is working on it, mainly via itsOptiGel Bio technology, which aims to put proteins,peptides, and other biological molecules—normallydelivered by injection—into an oral dosage form. One of

Patheon can take softgels from proof-of-concept, through clinical trials, and on tocommercial production.

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Seven of the top 10 best-selling drugpro ducts are biologics, but none of them isde livered orally, said Shinji Yamashita ofSetsunan University. “The oral delivery ofbiologics has attained a high level ofscience, but very few real-world products sofar.” Meanwhile, the science continues.

Researchers at the Massachusetts Insti -tute of Technology and Massachu settsGeneral Hospital have developed an oralcapsule coated with tiny needles that injectsdrugs into the lining of the GI tract.

In animal studies, the capsule deli veredinsulin more efficiently than sub cutaneousinjection, and its needles had no harmful sideeffects. In addition to insulin, the de vice maybe capable of delivering anti bodies to treatcancer and autoimmune disorders, as well asvac cines, recombinant DNA, and RNA.

Such biologics are difficult to deliverorally because their large molecular sizeprevents absorption in the GI tract. But thecapsule’s micro-needles overcome thatbarrier by directly injecting the pay load.Since there are no pain receptors in the GI,the injection is pain less. In tests on pigs, thedevice injected insulin into the stomachlining, small intestine, and colon. It tookmore than a week for the capsule to passthrough the digestive tract.

Although the needles had no harmful side effects, researchers are developing degradable needles that wouldbreak off, embed in the GI lining, and disintegrate as they release the drug.

Researchers are now developing a cap -sule with needles made of degrad able poly -mers and sugar. They would break off,embed in the GI lining, and slowly disin -tegrate while releasing the drug.

A summary of the study, “Micro needlesfor drug delivery via the gastro intesintaltract,” appeared online Sep tem ber 22, 2014,in the Journal of Phar maceutical Sciences.

— M.K.

Breaking the GI barrier with micro-needles

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the first candidates was a very low-molecular-weightheparin, which the company studied at one of itsEuropean R&D sites. “While that is not a large-molecular-weight API, the results show the promise of ourtechnology,” said Jeff Browne, Catalent’s R&D director ofpharmaceutical softgels in the USA.

The technology uses enteric-coated softgels to deliverthe API and permeation enhancers to the small intestine,where they open. “Once they reach the instestine, theyare designed to rupture quickly after dissolution of theenteric coat, even with the minimal volume of fluid thatyou have in the small intestine compared to thestomach,” he said. “After they rupture and the shelldissolves, the fill is released, providing a very high localconcentration of API and permeation enhancers at thearea of the GI where absorption can occur.” Thepermeation enhancers, typically medium-chain free fattyacids, are released from GRAS-listed ingredients in thefill formulation via normal biological processes, therebyopening the tight junctions between the GI cells. Thatallows the API to enter the bloodstream and exert itstherapeutic effect. “We can’t say this is the answer to

delivering all proteins and peptides orally, but we havethe promise of a technology that has shown what it cando for several model compounds that we’ve takenthrough animal studies.”

Catalent’s latest offering is OptiGel Lock, an abuse-resistant technology that enables companies to complywith recent FDA guidelines for preventing abuse ofopiates and other pain-management medications. “Whatwe’ve shown, through in vitro data primarily, is that wehave fill formulations and systems that are resistant toextraction and inhalation procedures that abusers use,”Browne said. “Basically, we think [the technology] meetsthe major criteria to claim that we have an abuse-deterrent product” for extended- and immediate-releaseproducts. He said many pharmaceutical companies arescrambling to comply with the FDA guidelines, which inmany cases will likely require them to reformulateexisting products. “Whether those are tablets or hardshellcapsules, we feel this softgel technology is as good orbetter than many of the other options on the market.”

Combination fills illustrate the flexibility of soft and hard capsules. Heremultiparticulates are combined with a liquid fill in a hard capsule.

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The GKF 702 from Bosch fills capsules with tablets, powders, pellets, and liquids,either individually or in combination. For powder fills, it uses either tamping pins ordosators.

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Catalent’s softgels include a variety of OptiGel technologies to deliverbiopharmaceuticals orally, deter abuse, and modify release. Its OptiGel Microsoftgels (bottom) are seamless and easy to swallow.

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Combinations and self-dosingAs the number of high-volume blockbusters fades and

pipelines dry up, pharmaceutical manufacturers areturning to new delivery methods and combinationproducts to extend the life of their brands. Last year,Capsugel introduced a “sprinkle” version of its Coni-Snapcapsules for use by patients who have difficultyswallowing. To access the fill—usually beads ormultipartculates—patients pull the capsule apart andsprinkle the contents over a soft food. Catalent offersOptiGel Mini, a technology for making very small,seamless softgels. They’re made at the company’s site inJapan, where consumers prefer small dosage forms. Mostare packaged in sachets or foil pouches, allowingconsumers to add them to food and to manage the dose.

To satisfy stronger demand for combination fills,Bosch offers equipment that fills as many as threedifferent types of materials, including powders, pellets,granules, tablets, and liquids, into a single capsule. Opitzsaid micro-tablets are an especially popular format.“Twenty years ago, there were a lot of new chemicalentities launched, and line extensions were not a focus forBig Pharma.” Today, however, as new APIs become lesscommon, the strategy has changed. “They’re nowreformulating their old APIs or combining them, andsince a lot of APIs are incompatible with each other theymust be conveyed using a different kind of formulation.”

T&C

References1. He, Xiongwei et al. Multi-compartment hard capsule and potential

applications. Poster W5133, American Association of PharmaceuticalScientists (AAPS) Annual Meeting and Exposition, San Diego, CA,November 2-6, 2014.

2. He, Xiongwei et al. DRcaps capsules banding for improved acidresistance. Poster W5132, AAPS Annual Meeting and Exposition, SanDiego, CA, November 2-6, 2014.

3. Youngster, Ilan et al. Oral, capsulized, frozen fecal microbiotatransplantation for relapsing clostridium difficile infection. JAMA, 2014Nov 5;312(17): 1772-8.

4. Straub, Hugues et al. Hard capsules for vaginal applications. PosterR6248, AAPS Annual Meeting and Exposition, San Diego, CA, November2-6, 2014.

5. Tardy, Claire et al. Capsules for dry powder inhalation—Performanceevaluation of different capsules with various inhalation devices. PosterT3174, AAPS Annual Meeting and Exposition, San Diego, CA, November2-6, 2014.

6. Dharap, Sonia et al. Understanding intra- and inter-individualdifferences in capsule puncture following actuation of a dry powder inhaler.Poster T3175, AAPS Annual Meeting and Exposition, San Diego, CA,November 2-6, 2014.

7. Diez, Fernando et al. Influence of temperature on capsule punctureperformance. Poster T3176, AAPS Annual Meeting and Exposition, SanDiego, CA, November 2-6, 2014.

8. Jones, Brian et al. The puncture properties and shedding of particlesof capsules in dry powder inhalers, effect of capsule type and moisturecontent. Poster T3178, AAPS Annual Meeting and Exposition, San Diego,CA, November 2-6, 2014.

9. Yamashita, Shinji. Ambition or just a dream? History and futureperspective for oral delivery of biologics. Presentation at AAPS Annual Meetingand Exposition, San Diego, CA, November 2-6, 2014.

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