Advances in capsule technology for pharmaceuticals and nutraceuticals.

This paper reviews some of the recent technical developments in capsule technology, including shell-forming materials and new applications, with reference to both pharmaceuticals and nutraceuticals. It also refers to ways in which capsule technologies are addressing issues associated with product abuse and counterfeiting.

Capsule technologies continue to develop and expand. The traditional powder-fill hard capsule (hardshell) and the liquid-fill soft capsule (softgel) still represent a significant percentage of the capsule market. However, the continuing development of materials and processing technologies for liquid-fill capsules offer increased options for formulators and manufacturers, and offers further opportunities for marketing groups. Materials development includes capsule-forming components and excipients that can affect product bioavailability and stability. Manufacturing technologies include machine development for new capsule-based units. These advances have been coupled with increasing manufacturing expertise and facilities to provide new product formats that can provide formulators and marketers with new options.

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New Materials

Capsule forming. Gelatin continues to be the main capsule-forming material, with ongoing activity in developing alternatives. One major development lies in non-gelatin softgel capsules that use modified starch in combination with carrageenans. (1) These are sulphated polysaccharides derived from the cell walls of red algae (such as Chondrus crispus) and are widely used in the food industry. Capsule forming uses the so-called iota and kappa carrageenans that have specific chemical and physical properties. The kappa carrageenan provides gel strength whereas the iota carrageenan provides flexibility. (2) They are suitable for concentrated fills or for salts of weak acids and strong bases, as shown in 18-month stability samples with ibuprofen. (3) It is likely that these materials will be exploited widely for non-gelatin softgel products.

Pullalan is listed as a new authorized Food Additive, E 1204 Pullalan according to EEC Directive 2006/52/EC. A naturally occurring water-soluble polysaccharide, it has film-forming properties suited to capsule formation and is the subject of ongoing development for non-gelatin hardshell capsule manufacture. It consists of a linear polymer of repeating maltotriose units comprising two (1 [??] 4) linked alpha-D glucose molecules followed by a (1 [??] 6) linked alpha-D glucose molecule. Pullalan is GRAS-listed in the US. (4) Its future use in EU pharmaceuticals will be controlled according to appropriate medicinal product submissions.

Hydroxypropylmethyl cellulose (HPMC) has become well established as an alternative to gelatin for capsule manufacture. Its marketing potential may be helped by an interesting (if unusual) recent regulatory change. It was classified on 1 January 2007 in the European Union as "organic" and defined as E464 (ingredient of plant or animal origin), with this description being applicable to capsules (effective as of December 2007). (5)

Capsule coating

Capsule coating has represented low-volume manufacture for many years, with restricted market opportunities. It has been aimed primarily at pharmaceuticals that required protection of the active against gastric acid. Commercial exploitation has been partly restricted by technological difficulties in ensuring robust processing and in adopting non-aqueous systems. For example, it is difficult to coat softgels because of low coat adhesion on the plasticized capsule shell surface; hence, coating is done using solvent systems. The use of hardshells minimizes this issue as there is no plasticizer present and the capsule surface provides for good shell/ coat adhesion. The cap/body edge can represent a mechanical weak-point for the coat but can be minimized by capsule banding (the Qualicaps Hicapseal system). It provides a nonstepped surface for coat adhesion and is suited for use with industry standard aqueous-coat materials. Unexpectedly, the enteric-coat components (copolymers of methacrylic acid and methyl methacrylate) which are standard to the pharmaceutical industry are not allowed in nutritional supplements. They could be useful in certain nutraceutical applications, such as for probiotics or other acid-sensitive components. An alternative approach that uses shellac in an aqueous-based system has been described. (6) It meets pharmacopoeial standards for entericcoat performance while meeting the acceptability requirements for non-pharmaceuticals. The system can be used on industry standard coating equipment such as Accelacota systems.

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Formulation components

Capsule development in pharmaceuticals is particularly associated with the expanding understanding of formulation routes using lipid-based materials, such as linoleolyl, lauroyl and oleoyl macrogol glycerides, and methods of using these to improve bioavailability through micro-emulsion systems. (7) These are thermodynamically stable homogeneous clear fluid systems that comprise an aqueous phase, an oily phase consisting of vegetable oils or fatty acid esters, a surfactant (such as non-ionics) and a co-surfactant (such as derivatives of propylene glycol or polyglycerols). They are being increasingly shown to improve the bioavailability of low-solubility and low-permeability compounds. Their design, applications and manufacture are beyond the scope of this article and the reader is referred to relevant chapters in a recently published major textbook on lipid-based dug delivery. (8,9)

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New Technologies Liquid-Filled Capsules

Richardson and Stegemann have reviewed the usefulness and manufacture of liquid-fill two-piece capsules. (10) The technologies for filling and sealing are well established, with there also being substantial ongoing technical developments in Process Analytical Technology (PAT) in controlling material viscosity and specific points of machine performance (temperature control and liquid tailing). (11) The number of pharmaceuticals using the technology is still small. However, there are a number of significant commercial products, ranging in annual volume scale from a few to hundreds of millions. For example, vancomycin capsules, developed in 1987, are important for the treatment of Clostridium difficile, which has become a major threat in hospitals in Europe and the USA. By industry standards, volumes are small but values are high. Certain high-volume products comprise materials recognizable in nutraceutical areas, such as the Nattermann product, Essentiale Forte capsules, which comprise phospholipids, linolenic, linoleic and oleic acid, as well as a blend of B vitamins. An Expanscience product, Piascledine capsules, comprises avocado and soya derivatives. There are, in addition, many nutraceutical products; for example, the French company Arkopharma manufactures and markets various oils containing Omega-3 and Omega-5 fatty acids. In practice, the technology continues to be seen as a niche area for volume production. Experience in this company does, however, indicate a high level of interest and activity in its application in the development of first-in-man studies and in the development and manufacture of high potency and cytotoxic products.

New Presentations

Difficulties concerning the development and manufacture of combination products have been the subject of recent discussion. (12) The Duocap system, developed for multicomponent and multiphase products, is based on hard-capsule liquid-fill technology and presents formulators with a means of solving these complex formulation issues, together with a way of implementing manufacture. Potential uses include

* the development of multiphase release products using specific excipients (macrogol glyceridesl) or technologies (microemulsions)

* the copresentation of compatible actives

* the copresentation of incompatible actives

* the avoidance of site-specific degradation in the gastrointestinal tract 

* the formulation of fixed-combination products

* meeting marketing needs for line extensions.

Based on manufacture using a modified Bosch 1500 L filling machine, the Duocap system enables a capsule (liquid-fill or powder-fill) to be filled into a larger liquid-filled capsule. As a further sophistication, either or both capsules may be coated. The approach is well suited to pharmaceuticals when there is a need to manipulate release profiles and to high-end nutraceuticals, particularly when there is a need to deliver product to different parts of the intestine or to avoid compatibility issues. The presentation may also have marketing advantage. The system may be applied to gelatin and HPMC capsules. Figure 1 shows an example in vitro data on nicotinamide/caffeine Duocap (gelatin capsule) formats, with and without enteric coating, to demonstrate the flexibility of the multiple capsule. In practice, an inner capsule, size X, is filled into an outer capsule, size X-2 (or larger) containing a liquid formulation (a size 0 capsule containing 0.140 mL of formulation could contain an inner size 2 capsule containing 0.325 mL of a second formulation, for example).

Technological application for probiotics

Probiotics are live microbial food supplements that may provide health benefits by improving the microbial balance of the intestine. (13) The main objective of use is to recolonize the gut--to protect against invading pathogens and to normalize gut flora after disturbance by antibiotics. The main commercial probiotic products are based on lactic acid bacteria, which are found in normal human flora and in dairy and grain products. The probiotic strains used are mainly intestinal isolates (Lactobacillus acidophilus, Lactobacillus casei, Enterococcus faecium and Bifidobacterium bifidum). Lactobacilli, in particular, are sensitive to heat and moisture. They are acid stable, with the preferred pH for growth being acidic. In nutraceutical oral dosage forms, the organisms are commonly maintained by freeze-drying and remain so until reactivated by the presence of water (when introduced into the intestine, for example). If simply reactivated by water in the absence of nutrients (during manufacture or on storage), the organisms activate and then die quite quickly, lowering product potency.

Potential Abuse    Water-Soluble     Lipid-Insoluble   Result
Route              Compound          Compound

Tampering of       (Band for         (Band for         Visual signal on
dosage unit        tamper-evidence)  tamper-evidence)  interference

Direct injection/  High-melting      High-melting      Non-injectable
melt/add water     water-soluble/    macro-            solidified mass,
                   thixotrope        golglyceride/     even when water
                                     thixotrope        is added

Powdered mass      Use high-melting  Use high-melting  Soft mass, not
                   but soft matrix   but soft matrix   possible to
                   that does not                       powder
                   powder; add
                   bitter taste
                   modifier

Extraction         Use base to       Use base to       Excipient and
                   match solubility  match solubility  taste modifier
                   profile of        profile of        'follow' in
                   compound; add     compound, such    extract
                   bitter taste      as macro-
                   modifier          golglyceride

Covert             Use 'floating'    Use 'floating'    Visible unit/
administration     carrier plus      carrier plus      taste
                   taste modifier    taste modifier    modification

Critical aspects of product quality relate to label claims and shelf-life for the types and numbers of viable organisms. Commercial products can be significantly sub-potent compared with label-claim and it is likely that one factor in these finding is the sensitivity of the organisms to moisture and heat. Products consisting of freeze-dried material in a standard gelatin capsule are exposed after manufacture to small levels of moisture via the capsule shell and this may lead to early activation, prior to administration. As the organism's activity is limited in the absence of other nutrients, any early activation can result in net loss of activity at later times in shelf-life and at the time of use. This sensitivity to moisture precludes their manufacture in gelatin softgels. However, they may be incorporated into a protective oily carrier in a low-moisture container. Here, a gelatin capsule format represents a convenient and reliable way of maintaining label claim during a realistic shelf-life (12 months).

Important aspects of product performance relate to the period for which it remains active and the point at which the organism activates in the body. The products are primarily for the delivery of viable organisms to the large intestine. Typically, a product will pass through the acidic conditions of the stomach, which may start early activation, as organism growth is promoted by acidic conditions. This may reduce the time of activity in the target area (the large intestine). One option to counter this is through enteric coating. Unexpectedly, standard pharmaceutical enteric coat components, such as Eudragit, are not allowed in nutritional supplements and such coating needs an alternative approach--a shellac-based coat in an aqueous medium using standard (Accelacota) equipment, for example. The commercial product Travelguard (Biocare) uses Duocap technology to present Lactobacillus acidophilus and Bifidobacterium bifidum as probiotics in a suitable oil--in an entericcoated inner capsule inside a larger capsule--which contains a mixture of 'digestive' oils that would otherwise be incompatible with the probiotic content. Here, the coat is suited to nutraceuticals and is considered to protect the probiotic from the acidic conditions of the stomach.

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A further technological sophistication for improving product quality for probiotics lies in the use of an HPMC capsule format. These shells contain less than half of the moisture of gelatin capsules stored under the same conditions. At 50% RH, gelatin holds approx 14% water whereas HPMC hold 5%. The probiotic content can be hydrophilic (as a dried material) and extract moisture from the shells, causing early activation and net loss of shelf-life. Additionally, loss of moisture from a gelatin shell may cause embrittlement and cracking of the shells, again reducing shelf-life. HPMC is very resistant to dehydration and embrittlement conditions and may be an overall better choice for materials such as freeze-dried probiotics. The use of an HPMC shell may therefore offer advantages in maintaining product viable counts and product elegance, so complying with label claim needs and extending shelf-life.

Anti-Abuse and Anticounterfeiting

Standard pharmaceuticals are developed for the supply and use of approved products according to authorized prescribing. Increasingly, however, development and manufacturing groups have to consider issues relating to product abuse that affects personal safety and to product counterfeiting, which affects both user safety and commercial integrity. Product abuse may comprise part of an individual's drug-dependence/addiction habit. There has been concern regarding the criminal "spiking" of a third party's drink, but this has been described recently as being anecdotal, rather than substantiated. A product's sensitivity to abuse may be enhanced by the formulator's initial intention in meeting particular bioavailability profiles. Anti-abuse design aims at two major ways of minimizing abuse risk. One is to make the mechanics of manipulating the dosage form sufficiently complex that the potential abuser will avoid the product, effectively minimizing the extent of that abuse. The other is to minimize the acute hazard generated by intentional personal interference, such as by dose-dumping an opiate from a high-dose controlled-release format. These aims have to be achieved while still maintaining standard product attributes for normal use; that is, providing the designed release profile. Clearly, there are limits to which this can be successful, as a really determined or skilled individual will find ways of circumventing the design intention. Development studies have explored various ways in which the capsule dosage unit can be made less vulnerable to abuse (Abusolve) and the approaches are summarized in Table I.

This type of abuse is likely to have a significant clinical effect on small numbers of people. Counterfeiting, by contrast, is likely to affect large numbers of people; delivering subpotent product has become the subject of widespread criminal activity affecting many product types. The availability of pharmaceutical products through the Internet reduces the traditional industry control on the integrity of national and international supply chains. Nevertheless, the industry is investigating ways in which each of these issues may be minimized. Parish has described anticounterfeiting measures for tablets and capsules, for example, using laser imaging and two-dimensional barcodes that are invisible but machine-readable. (14) Packaging innovations will also contribute to this process. Radio-frequency identification (RFID) of packages has been explored but has already been the subject of interference with respect to tracking the chips or tags. Other mechanisms such as the micro-colour-coding of dosage units or packs may, however, turn out to be more practicable, robust and resistant to interference. (15)

Summary

Capsule development continues across a broad spectrum of activities, ranging from the introduction of new materials, through new formulation and processing systems and up to meeting the security needs of the current marketplace. These reflect engineering and formulation innovations and the market's needs to resolve increasingly demanding technical issues in the development and manufacture of products containing new chemical entities or drug combinations, while also accounting for issues of product abuse and counterfeiting.

Acknowledgement

The authors thank Dr Lubna Arif for her helpful comments in preparing this paper.

References

(1.) US Patent 6,375,981 (2002).

(2.) European Patent EP1474115 (2004).

(3.) US Patent 20,060,099,246 (2006).

(4.) Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food, EFSA Journal 85, 1-32, (2004).

(5.) Official Journal of the European Union, Regulation 780/2006 (2006).

(6.) US Patent 20,070,071,821 (2007).

(7.) H. Benameur, Bull. Tech. Gattefosse 99, 63-75 (2006).

(8.) M. Grove and A. Mullertz, "Liquid Self-Emulsifying Drug Delivery Systems," in D. Hauss, Ed., Lipid-Based Formulations for Oral Drug Delivery (Informa Healthcare, New York, New York, USA, 2007) pp 107-128.

(9.) W. Bowtle, "Materials, Process and Manufacturing Considerations for Lipid-Based Hard-Capsule Formats," in D. Hauss, Ed., Lipid-Based Formulations for Oral Drug Delivery (Informa Healthcare, New York, New York, USA, 2007) pp 79-106.

(10.) Richardson and Stegemann (www.capsugel. com/pdf/Filling_Two-Piece_Hard_Gelatin_Capsules_with_Liquids) 2007.

(11.) F. Nink, Pharm. Man. Pack. Sourcer (Summer 2007) pp 42-47.

(12.) S. Frantz, Nat. Rev. Drug Discov. 5(11), 881-882 (2006).

(13.) P. Mason, Pharm. J. 278, 373-376 (2007).

(14.) G.L. Parish, Tablets and Capsules 2(4), 36-43 (2005).

(15.) N. Golomb, Pharm. Man. Pack. Sourcer (Summer 2007) pp 62-66.

Dr Stephen Brown is R&D Director at Encap Drug Delivery. He obtained a Pharmacy degree from the Queen's University of Belfast in 1979 and, during the following years, has held positions in R&D, Technical Services and commercial manufacturing for a number of pharmaceutical companies (Sterling Winthrop, Sanofi, Chiroscience and Celltech) in the UK and the US. During the course of his career he has been involved in the development and commercialization of a wide range of drug products and drug delivery technologies. Immediately prior to joining Encap Drug Delivery he was Director of Product Technology Development for UCB Celltech.

Bill Bowtle is Technical Director of Encap Drug Delivery, Livingston, UK. Before establishing the company in 1989 to offer specialty contract development and manufacturing for liquid-fill capsules, he worked with Eli Lilly, where he was responsible for the development of the first commercial product based on hard-capsule liquid-fill technology using thermosoftening materials. His experience includes the development and implementation of liquid-fill capsule manufacturing systems, including validation and quality assurance.

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