Starch Capsules

1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00238-2

▼ In the early 19th century, Mathes developedthe first capsule dosage form from gelatin: analternative to the traditional tablet dosage form.Since then, this technology has been continuallyimproved and refined, yielding the range of cap-sule forms available today. There have been at-tempts to find other substances to replacegelatin, although the successful manufacture ofstarch capsules has only recently been achieved.The starch capsule, a unique solid oral dosageform, is made of potato starch and represents adirect alternative to hard gelatin capsules. In thesearch for an alternative process to the dipmoulding of gelatin capsules, Capsugel®, a divi-sion of Warner Lambert, investigated and devel-oped an injection moulding technique for themanufacture of starch capsules (Capill®), thestarch capsules currently manufactured by WestPharmaceutical Services.

In some respects, the starch capsule can be considered to be equivalent to the hard gelatincapsule. However, starch capsules feature severaladvantages: dissolution is independent of pH, theyare suitable for enteric coating1, moisture in theshell is tightly bound to starch, and the capsulesare tamper-evident2 and preservative-free andproduced from non-animal-derived ingredients2.

Hard shell capsules made of potato starch con-sist of two pieces, a cap and body, which aresealed together at the time of filling to preventseparation (Fig. 1). Sealing is achieved by apply-ing a hydroalcoholic solution to the inner sectionof the cap, immediately prior to its being placedonto the body.

Manufacturing processRecent advances in injection moulding technol-ogy have permitted the manufacture of starch cap-sules.Various authors have described the processin detail1,3,4, and Fig. 2 illustrates the essential partsof a conventional injection-moulding machineused. During the production process, starch – inthe form of powder, granules or pellets – is fedthrough the hopper onto a rotating reciprocatingscrew.The feed material moves along the screw to-wards the tip. During this process the temperatureis increased by means of external heaters aroundthe outside of the barrel and by the shearing ac-tion of the screw. From the feed zone to the com-pression zone, the feed material is graduallymelted down; it is then conveyed through the me-tering zone, where homogenization of the meltoccurs, to the end of the reciprocating screw.When sufficient melt is collected for injection, itis injected into the mould. The rotation of thescrew stops while the polymer in the mould coolssufficiently for the mould to be opened and themoulded parts ejected. Pressures of between700–2000 bar and temperatures of between120–1808C are normally seen in the transport, in-jection and moulding operations.Throughout theprocess the mould is maintained below the glasstransition temperature of starch, and the time fora complete cycle is usually a few seconds.

Capsule fillingAs starch capsule caps and bodies are manufac-tured separately, existing capsule filling machines

Starch capsules: an alternative systemfor oral drug deliveryVinod D. Vilivalam, Lisbeth Illumand Khurshid Iqbal

Vinod D. Vilivalam*Lisbeth Illum

and Khurshid IqbalDrug Delivery Systems

West Pharmaceutical Services101 Gordon Drive

Lionville PA 1934 USA*tel: 11 610 594 3157fax: 11 610 594 3016

e-mail: [email protected]

reviews research focus

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PSTT Vol. 3, No. 2 February 2000

Manufactured by the process of injection moulding, starch capsules

have been shown to be a very useful alternative delivery system for

orally administered compounds. This review describes the starch cap-

sule manufacturing and filling processes and provides an overview of

the capsules’ physical characteristics. In addition, investigations sup-

porting the development of novel delivery technologies based on the

starch capsules are described. Particular emphasis is given to a tech-

nology that facilitates drug delivery to specific sites in the human

gastrointestinal tract.

require some modification for the filling and sealing of thestarch capsules.Two types of machines are available for the fill-ing of starch capsules; a semi-automatic bench-top filling ma-chine for laboratory development, and a production-scaleBosch™ (GKF) 400C filling machine (Bosch, Minneapolis,MN, USA). Using a bench-top filling machine, 20 capsules canbe filled or sealed at a time. In a fully automated Bosch GKF

400C, the normal output is approximately 270 capsules perminute when filling powder or pellets, and approximately150–180 capsules per minute for the filling of semi-solids.

Physical characteristicsStarch capsules can be manufactured in different sizes – sizenumbers 0, 1, 2, 3 and 4 – by changing the moulds (Fig. 3).An essential advantage of the capsule design is that the same-sized cap is used to fit different body lengths.The diameter ofthe junction of the cap and body is always the same on all sizesof starch capsules. Unlike the ‘lipped’ seal on a gelatin capsule,the starch capsule cap fits evenly in place over the body, lead-ing to a good surface finish. This is a further advantage as thecapsules are easily tamper-evident.The starch capsule is odour-less and rigid, and exhibits similar dissolution behaviour to thegelatin capsules. In vitro release studies of acetaminophen, as amodel drug, using the United States Pharmacopeia (USP)Apparatus 2, demonstrated that the release properties of starchcapsules were independent of pH (West PharmaceuticalServices, unpublished).

The storage conditions, especially the humidity, have signifi-cant influence on the integrity of all types of capsules.Typically,the moisture content of the starch capsules ranges between12–14% w/w, with more than 50% being tightly bound to thestarch. The presence of bound moisture suggests that starchcapsules may provide better stability properties and reducedsusceptibility to changes on storage. Starch capsules, containing

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PSTT Vol. 3, No. 2 February 2000 reviews research focus

Figure 1. Starch capsules (cap and body). The cap is designed to fit thebody with a smooth seal.

Figure 2. Schematic representation of the starch processing parts of injection moulding equipment.

Pharmaceutical Science & Technology Today

Nozzle Check ring

Screw

Hopper

Barrel

Meteringzone (25%)

Compressionzone (25%)

Feed zone (50%)

acetaminophen, were studied for stability in PVC-PVdC-Alublisters and high-density polyethylene (HDPE) bottles. PVC-PVdC-Alu blister is a type of pharmaceutical packaging thatuses aluminum blisters to package each starch capsule.The PVC(polyvinyl chloride) is coated with PVdC (polyvinylidene chlo-ride) to improve water vapour and oxygen protection. The results of this study suggest an acceptable stability profile after18 months in both packages (West Pharmaceutical Services,unpublished).

Enteric-coated starch capsulesThere is considerable interest in the enteric coating of pharma-ceutical preparations for drug delivery to the intestinal re-gion5,6. Such coatings have been traditionally reserved for drugsubstances that cause gastric irritation, produce nausea orwhich are destroyed by acid or gastric enzymes. Recently, func-tional coatings have been applied to dosage forms intended fortargeted delivery, especially to the colon7.The delivery of drugsto the colon has applications in several therapeutic areas.Theseinclude the topical treatment of colonic diseases and the oraldelivery of drugs destroyed in the upper gastrointestinal (GI)tract. Many diseases of the colon, such as ulcerative colitis,Crohn’s disease and irritable bowel syndrome, could be bettertreated when site-specific delivery of the therapeutic agent iseffective.

There have been considerable technical problems in themanufacture of coated hard gelatin capsules, especially sincethe advent of aqueous coating systems8. For example, during

coating with aqueous spray formulations, the gelatin shell canoften soften and become sticky because of solubilization, orbrittle as a result of water evaporation and drying, especially atthe onset of coating. In addition, there are difficulties associatedwith the coating of the ‘lipped’ hard gelatin capsules, whichcould compromise the protective characteristics of the coating(West Pharmaceutical Services, unpublished). The coating ofstarch capsules appears to be less problematic because of thesmooth seal of the filled unit, coupled with the higher bulkdensity of the capsules, which provide for a more uniformcoating bed.

Studies have been performed to evaluate the stability of thecoated starch capsules. Brogmann et al. compared the stability ofenteric-coated gelatin and starch capsules using aqueous dis-persions of methacrylic acid copolymers9.The results obtainedindicated the presence of a smooth and glossy coating layer onstarch capsules.The hardness of the coated starch capsules wasfound to be 280 Newtons (N), and no cracks or separation ofthe coating from the capsule shell were observed during hard-ness testing. In contrast, only a modified formulation, with ahighly controlled procedure, resulted in an acceptable smoothcoating on gelatin capsules, with a relatively lower hardnesslevel of 65 N.The coated starch capsules also demonstrated anexcellent stability profile for 12 months at room temperatureand at 378C, as well as gastroresistance and disintegration in theintestinal fluid.

The stability of enteric-coated starch capsules was studied byVilivalam et al. using 5-ASA (amino salicylic acid) as a model

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PSTT Vol. 3, No. 2 February 2000reviews research focus

Figure 3. Engineering drawing of the available sizes of starch capsules.

0.70

0′′ [

17.7

9 m

m]

0.27

5′′

[6.9

9 m

m]

0.53

8′′ [

13.6

7 m

m]


0.22

7′′

[5.7

7 m

m]

0.333′′[8.47 mm]

Size 0 Size 1

0.41

9′′

[10.

63 m

m]

Size 2

0.35

7′′

[9.0

6 m

m]

Size 3 Size 4

drug10.The capsules were evaluated in terms of coat integrity atvarious time points by testing for drug release and disinte-gration, using the USP dissolution and disintegration apparatus.The study design included the development of processing con-ditions to enable coating using a solvent-based coating systemcontaining Eudragits® in a perforated pan coater (Hi-Coater®,Vector Corporation, Marion, IA, USA), and to evaluate in vitrodissolution and disintegration changes on storage at 258C and55% RH and 408C and 75% RH.The capsules were successfullycoated using this system, and visual observation indicated auniform and smooth seal, especially at the junction of cap andbody. The 5-ASA release remained unchanged for 24 weeks(408C and 75% RH), as seen in Fig. 410.The coated capsules re-mained intact in gastric medium, and reproducibly disinte-grated at between one and two hours after insertion in intesti-nal medium.

In another study,Vilivalam et al. used an extrusion–spheroni-zation process to develop 5-ASA beads designed to deliver thedrug to the colonic region using the coated starch capsules11.The in vitro release showed that the uncoated starch capsules hada slower rate of 5-ASA release compared with unencapsulatedbeads; this was because of the required capsule disintegration.The enteric-coated capsules showed an increased lag time in 5-ASA release because of slower disintegration.The 5-ASA releasefrom the beads modelled a Higuchi’s square-root time model,indicating diffusion as the primary mechanism of release.

Burns et al. compared in vitro release profiles of non-entericand enteric-coated liquid-filled starch capsules with that ofgelatin capsules using a lipophilic model drug, propanalol12.Initial studies indicated that some of the liquid-filled starch

capsules leaked. The leakage was overcome by modifying theformulation to incorporate a thermosoftening agent, such asGelucire™ 33/01 (polyglycolysed glyceride) (Gattefosse, Saint-priest, France). The dissolution profiles of the non-enteric-coated capsule formulations indicated similar biphasic releasecharacteristics to both hard gelatin and starch capsules. How-ever, the dissolution profile for enteric-coated starch capsuleswas considerably slower than that of coated hard gelatin cap-sules. An increased concentration of bile acid (14 mM as op-posed to 7 mM) was incorporated into the dissolution mediumto test for its effect on the rate of propanalol release fromcoated starch capsules. The subsequent change in the dissolu-tion method produced a similar release profile to that seen forenteric-coated gelatin capsules containing the same formu-lation.The authors concluded that starch capsules represent analternative dosage form for complex formulations such as theHALO™ delivery system12, a drug–oleic acid solution with abiphasic release characteristic, particularly where reliable en-teric coating is of prime importance.

Scintigraphy studiesGamma scintigraphy has been routinely used to follow thetransit and release characteristics of dosage forms in the humanGI tract13. Scintigraphy techniques were used to confirm the invivo behaviour of starch capsules compared with traditionalhard gelatin capsules14. Doll et al. studied capsule opening andGI transit times for hard gelatin and starch capsules in humanvolunteers14. The GI transit data were correlated with drug(amoxicillin) plasma concentrations. In each study, a starchcapsule and a gelatin capsule, each containing 250 mg of

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Figure 4. Release profiles of 5-ASA fromenteric-coated starch capsules (stored for up to24 weeks at 408C and 75% RH). Initial timepoint (open circle); Four-week time point (closedsquare); 12-week time point (closed triangle);24-week time point (closed circle). Adaptedfrom Ref. 11.


20.0

15.0

10.0

5.0

0.00.0 1.0 2.0 3.0 4.0

Time (h)

5.0 6.0 7.0 8.0

Am

ount

of 5

-AS

A r

elea

sed

(mg)

amoxicillin and a radiolabel, were administered under fastedconditions. Analysis of the GI transit and plasma amoxicillindata showed no statistical difference between the starch andgelatin capsules in normal human volunteers.

Wilding et al. used gamma scintigraphy in a study designedto evaluate the GI transit and in vivo disintegration characteristicsof Aquateric™-coated starch capsules in eight healthy subjectsunder fasted and fed condition15. Aquateric is a completelywater-based reconstituted dispersion of cellulose acetate phtha-late (CAP) latex. The product is sold as a dry, white, water-insoluble powder, which may be dispersed in water to create an enteric film-coating liquid. No loss of capsule integrity wasobserved in the stomach following administration, after eitheran overnight fast or a medium breakfast, thereby confirmingthe gastroresistant properties of the coated capsules. Initial signsof capsule disintegration were observed in the small intestine.Once disintegration had commenced, complete break-up oc-curred, on average, within 20 minutes.The study also includeda test on the effect of food on the in vivo behaviour of an aque-ous enteric-coated starch capsule formulation16. In vitro disinte-gration testing showed that the coated capsules remained intactin 0.1 N hydrochloric acid for more than two hours, but disin-tegrated within 20 min after the acid medium was exchangedfor pH 6.8 phosphate buffer. Gamma scintigraphy confirmedthe gastroresistant properties of the coated starch capsules andthat they remained intact in the stomach until disintegrationoccurred in the small intestines at 66 6 28 and 95 6 3.3 min-utes (average 6 standard deviation) respectively, after leavingthe stomach, following fasted and fed administrations.

The use of starch capsules in conjunction with a variety ofcoatings, such as a pH-sensitive material, a redox-sensitive ma-terial, or a material broken down by specific enzymes or bacte-ria present in the colon, for site-specific delivery to the colon isthe subject of a patent filed in Europe, USA, Japan and otherterritories17. Watts et al. designed an enteric-coated starch cap-sule system (TARGIT® technology) for targeting specific siteswithin the colonic region17.The coating employed is based ona mixture of Eudragit™ L and S, chosen to provide a coating thatstarts dissolving when the capsule enters the small intestineafter leaving the stomach. The thickness of the coating can bedesigned so that the capsule disintegrates within a predeter-mined region in the intestine, such as the terminal ileum, theascending-, the transverse-, or even the descending colon.TheTARGIT delivery system therefore works by both a pH andtime-dependent mechanism, which is considered to be morefail-safe than systems depending only on a pH change in theenvironment (Fig. 5).The TARGIT system has been tested witha range of drugs in several Phase I clinical trials involving bothgamma scintigraphy and pharmacokinetic studies, and hasachieved targeting to the colonic region7.

Regulatory statusCapsules prepared from starch are officially recognized inUnited States Pharmacopoeia 23 and National Formulary 18(Ref. 18). The USP also permits the use of colouring agents,opacifying agents such as titanium dioxide, dispersing andhardening agents, as well as preservatives. European pharma-copoeias do not specifically include starch as an ingredient incapsules. Instead, the wording is ‘capsule shells are composedof gelatin or other materials.’

ConclusionRecent advances in injection moulding technology have facili-tated the manufacture of starch capsules.Various physical char-acteristics have indicated that starch capsules are, in some ways,comparable with those of gelatin capsules; however, starch cap-sules have some noted advantages. This type of capsule mayprove to be a useful alternative to its gelatin counterpart. Theenteric coating of starch capsules is a successful approach totargeted intestinal drug delivery, especially with drugs that can-not be compressed into tablets. In addition, starch capsules inthe form of TARGIT® will deliver formulations to the terminalileum or colon, and provide the means for local drug deliveryfor the treatment of diseases such as ulcerative colitis, Crohn’sdisease or irritable bowel syndrome. It is also envisaged thatthe TARGIT® system will facilitate vaccine delivery to the large

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Figure 5. Scintigraphic images of a radiolabelled TARGIT® capsule in ahuman following oral administration. At zero hours the capsule is inthe stomach (a); one hour (small intestine) (b); 3.5 hours (ascendingcolon) (c); and 8.5 hours (dispersed in transverse and descending colon)(d). Adapted from Ref. 7.

bowel for mucosal vaccination. It is known that the colon isrich in lymphoid tissue and that the creation of a high localantibody response is feasible. Additionally, the outbreak ofbovine spongiform encephalopathy (BSE), or mad cow’s dis-ease, there is concern about the quality of certain animal prod-ucts involved in the production of gelatin capsules19. As analternative, starch is a viable option because of the absence ofproducts of animal origin.

AcknowledgementsThe authors wish to thank the following individuals for their as-sistance: S.S. Davis and Lisa Nolan for their comments and criticalreview of the manuscript; Nick Klutcka for his insights on themanufacture of the injection-moulded capsule; Ryan Waddell andDavid Howe for their assistance in the research and development.

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5 Hardy, J.G. et al. (1987) Evaluation of an enteric-coated delayed-release 5-

aminosalicylic acid tablet in patients with inflammatory bowel disease.

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23, 893–913

8 Plaizier-Vercammen, J. et al. (1992) Enteric coating properties of Eudragit®,

Aquateric® and Cellulose Acetate Trimellitate applied to capsules. Eur. J.Pharm.

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extrusion-spheronization process for colonic drug delivery using starch

capsules. Pharm.Res. 1, S-645

12 Burns, S.J. et al. (1996) An in vitro assessment of liquid-filled Capill® potato

starch capsules with biphasic release characteristics. Int. J.Pharm. 134, 223–230

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14 Doll,W.J. et al. (1993) A scintigraphic and pharmokinetic evaluation of a novel

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gelatin capsule in normal and in normal subjects administered omperazole.


15 Wilding, I.R. et al. (1993) Enteric coated starch capsules:A new approach for

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WO35100

18 USP23/NF18 (1995) Capsules, ,1151. Pharmaceutical dosage forms, pp.

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19 Guidance for Industry (1997) The sourcing and processing of gelatin

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Starch Capsules