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Technology & Services
Advances in Liquid Fill Capsule Technology
a report by
William Bowtle
Technical Director, Encap Drug Delivery Ltd
The commercial pharmaceutical and nutriceutical capsules at Encap Drug Delivery has shown that the
markets have driven the development of alternative format is also suited to novel capsule applications.
forming materials for the traditional capsule shell
material gelatin. The on-going establishment and Chewcaps™
further development of the manufacturing
technology for liquid fill capsules have provided an Encap Drug Delivery has explored various
enabling base for certain new applications for oral formulations for ‘chewable’ capsules containing a
drug delivery, especially for lipid-based systems. This range of flavours. The mouthfeel is agreeable as the
report comments on costs and describes some recent capsule body is crushed and folded into the flavoured William Bowtle is Technical Director
product applications for two-piece capsule liquid fill matrix by chewing. Gelatin capsules simply fracture, of Encap Drug Delivery Ltd, UK. His
main current responsibilities are in
systems including DuoCap™, ChewCaps™ and creating a very uncomfortable sensation. Several new product development for client
Organic Sachet™. It also refers to alternative sources other issues arise during formulation work: companies. Mr Bowtle has extensive
experience in formulation and
for gelatin. processing in a wide range of liquid
• the suitability of the matrix for the mechanics of fill applications, including
Costs chewing (hardness/brittleness/chewability); improvement of bioavailability,
controlled release formulations and
cytotoxic products. He was
A common question in early consideration of liquid- • the duration of residence in the mouth; responsible for the development of
the first commercial thermosoftening
filled capsules is their cost in relation to other oral
capsule product using two-piece liquid
dosage forms, for example powder capsules, coated • the ability to mask taste; and fill capsule technology. Mr Bowtle
tablets and, for controlled release products, pellet-filled later established the independent
company specialising in the contract
capsules. Cost components include those for • the taste of the shell. development and manufacture of
development, plant and raw materials. For liquid-filled two-piece capsules.
development and manufacturing purposes, it is widely Here, the permeability of the HPMC product is an
recognised that liquid fill capsules are significantly less advantage. Typically, gelatin capsules do not transmit
demanding of environmental and Good odour. For a chewable, where taste is significant to
Manufacturing Practice (GMP) compliance user acceptability, the perceived flavour may be
requirements for potent or cytotoxic drugs than enhanced by perception of the product odour on
standard capsule or tablet formats, due to their not opening the (bulk) pack.
generating dust. This has major impact in reducing
costs associated with dedicated rooms, buildings and Organic Sachet™
air handling and in simplifying handling procedures.
Scale-up costs are minimised since the filling/sealing Larger-volume (3–5ml) HPMC capsules are now
processes are achievable on the same full-scale also becoming available commercially. Although not
equipment from batch sizes of 3,000 capsules upwards. currently being aimed at use in humans, they may
have other applications, for example as a disposable
Approximate capital costs for full-scale equipment container for, say, single-use toothpaste. Their
are in the order coated tablet – liquid-fill or pellet-fill physical size would preclude them from being used
capsule – powder-fill capsule. Current full-scale for consumption and this, in itself, opens up other
running costs are also likely to decrease with the possibilities. They have the advantage that they are
current development of larger-capacity filling cold water-soluble and are therefore suitable for
machines (for example Bosch) and of integrated simple (domestic) disposal. The appearance of empty
filling/sealing machines (Shionogi). uncoloured capsules is amber, cf. bright colourless.
This is unlikely to be an issue where the shell is being
New Capsule Applications used as a non-consumed container. The capsules
may, of course, be coloured and printed.
The development of systems for processing of
hydroxypropyl methylcellulose (HPMC) liquid-filled One remaining issue for HPMC capsules is their 1
BUSINESS BRIEFING: PHARMATECH 2003
Technology & Services
Figure 1a: In Vitro Release from Duocap™ Capsules an initial elevation of plasma level and then provide
for appropriate prolonged elevated plasma level. The
format may also be useful in avoidance of site-specific
degradation in the gastrointestinal tract,
improvement of patient compliance and avoidance
of compatibility issues for multicomponent products.
Commercially, they are also important in meeting
marketing needs for line extensions.
Their preparation is often complex at bench level
and proportionately difficult at manufacturing scale.
Using its liquid fill technology for hard capsules,
Encap Drug Delivery has developed a practicable and
convenient formulation system that is well suited to
such multiphase products (DuoCap™). It has also
designed and built machine modules that enable full-
scale manufacturing on Bosch-based equipment. It
enables a capsule (wide range of formats, including
coated) to be filled into a larger liquid-filled capsule,
Figure 1b: DuoCap Capsules which may, in turn, be coated. The approach is well
suited to formulating and filling formulations with
various functions:
• specific in vitro release requirements (pulsatile or
bimodal);
• avoidance of site-specific degradation in the
gastrointestinal tract;
• improvement of patient compliance;
• compatibility issues for multicomponent products;
and
• marketing needs for line extensions.
Examples of in vitro data are shown in Figures 1 and 2
for nicotinamide/caffeine gelatin capsule formats,
with and without enteric coating on the inner
suitability for particular markets. All are suitable for capsule, to demonstrate flexibility of the DuoCap™.
nutriceutical markets but some may have restricted
pharmaceutical application due to specific technical Targeted Lymphatic Delivery
issues, for example solubility characteristics at low
pH. One supplier (Shionogi) has declared Drug delivery to the intestinal lymphatic system has
compliance of its materials with pharmacopoeiae in been highlighted for commercial development.1 The
the US, Europe and Japan. area has been the subject of extensive academic work
but little commercial exploitation. It aims to improve
DuoCaps™ the absorption of low-solubility/lipophilic compounds
through lymphatic absorption. Systems include
Multiphase Delivery in Gelatin or microemulsions and self-emulsifying systems and are
HPMC well suited to liquid fill capsule-based dosage units.
Commonly, a multiphase oral format is required to Microemulsions are important for low-solubility
meet clinical needs for specific plasma time course compounds. They are homogeneous, clear fluid
profiles of compounds with biological half-lives in systems comprising an aqueous phase, an oily
the order of one to six hours, for example to produce phase, a surfactant and a co-surfactant. They are
1. C O’Driscoll, “Drug delivery to the intestinal lymphatic system’’, The Drug Delivery Companies Report, Spring
2 2002, pp. 32–38.
BUSINESS BRIEFING: PHARMATECH 2003
Advances in Liquid Fill Capsule Technology
formed spontaneously on gentle mixing, are Figure 2a: In Vitro Release from Duocap™ Capsules,
thermodynamically stable and of low viscosity. Enteric-coated Inner
These properties make them potentially suitable for
drug formulation, for example cyclosporin. Their
transparency is due to the small droplet size
(100–600nm) formed by the oil, water and
amphiphile. Their use had previously been
restricted due to the toxicity of the various
surfactants but is now well established. Typical
components are non-ionic surfactants, derivatives
of propylene glycol or polyglycerols (present as co-
surfactants) and vegetable oils or fatty acid esters
(present as the oily component).
The proportions of the components are established
using pseudo-ternary phase diagrams to map out the
microemulsion domain. The proportions in which
the fluid remains clear define the range of mix
proportions that are potentially viable. It is important
as a next step to ensure that these mixes are
compatible with hard capsules since excessive levels Figure 2b: Fish Oil Capsules Coated with Acryleze and Opadry
of particular components may cause shell
embrittlement and failure.
Such groups as Gattefosse have developed self-
emulsifying drug delivery systems. They generally
contain an oil or lipid-related material, a surfactant
and may contain a co-surfactant. They are
applicable for substances with low water solubility.
For example, combinations of acetylated
monoglycerides and various high and low
hydrophilic/lipophilic balance carriers can be used
to give a self-emulsifying system for certain low-
solubility materials. There are many examples in the
literature. Such systems have been used and widely
studied for specific high-cost compounds, for
example cyclosporin. They could, however, be
used for more common drugs such as flurbiprofen.
Capsule Materials
Fish Gelatin
Bovine Gelatin
Capsules made from fish gelatin have become
Animal gelatin, derived from the collagen of bone available recently on a commercial scale. Roxlor
and skin, is the historical major material for two- (France) has started manufacture of these products,
piece capsules. It presents a number of issues in using gelatin derived from fish skin. The gelatin used
manufacture and use, including technical, regulatory, here is derived from warm-water (cf. cold-water)
commercial and consumer acceptability aspects. species since the levels of originating proline and
Major companies routinely consider transmissible hydroxyproline (significant to gelling characteristics)
spongiform encephalopathy issues for potential in their collagen more closely resemble the levels in
components during product development. The mammalian collagen. The specified chemical and
industry has well-established procedures to ensure physical characteristics of these capsules match those
the safety and suitability of pharmaceutical gelatin. for gelatin products from other manufacturers,
Nevertheless, the commercial availability of suitable enabling them to be run on standard machines for
alternatives has been considered a major requirement two-piece capsules. Importantly, their so-called
for both pharmaceuticals and nutriceuticals. Their acceptable quality level attributes for incidence of
availability and potential use have been reviewed.2 defects match those for products from other capsule
2. W Bowtle, ‘’Options in materials for liquid-filled capsules’’, Pharm. Manuf. Pack. Source, 2002 (2), pp. 78–81. 3
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Technology & Services
suppliers, ensuring similar product quality. equipment. They do differ in detailed structure, with
Experience in this company indicates that they are there also being differences in specific quality
well suited to the liquid fill format. characteristics. Their use for liquid fill products is
commercially attractive but has been restricted until
Human Gelatin recently due to technical issues in their sealing. Encap
Drug Delivery has developed formulation and
Longer term, availability of ‘human’ gelatin, manufacturing systems that provide for robust high-
produced from recombinant human collagen, may speed liquid fill processing, matching the quality
provide a suitable low-cost gelatin for shell standards of gelatin capsule products.
manufacture. FibroGen, Inc. (San Francisco) has
developed transgenic plant expression technology that The Future
can produce gelatin precursor collagen. Their current
aims are for cGMP manufacturing of ‘human’ gelatin, It is important for capsule technology development
with consistent high quality and no potential to offer flexibility of materials and delivery systems to
contaminants. Commercial exploitation will depend meet scientific and fast-moving commercial markets.
on the development of systems for large-volume, Formulation approaches such as microemulsions can
high-quality product. To this end, FibroGen and be expected to be used for novel low-solubility
Prodigene have announced collaborative work on compounds and for extending patent lives of older
production of such recombinant gelatin in maize for compounds. Other means of targeted delivery and
high-volume/low-cost bulk material. new carrier systems also offer potential wide
application. For example, colonic delivery may be
HPMC feasible for capsule formats using amylose/
ethylcellulose coating systems. Solid lipid
HPMC represents the current major alternative nanoparticles, derived from warm oil-in-water
material for two-piece capsule shells. Their microemulsions and with drug loading up to 25%,
commercial manufacture differs from that for gelatin offer the interesting possibility of using a new
shells, with the producers (Capsugel, Shionogi delivery vehicle that targets lymph and is likely to be
Qualicaps and Su Heung) using differing techniques compatible with liquid capsule technology.
to solve specific issues, for example use of differing
additives and mechanical processing techniques. The The two-piece liquid fill capsule format is well suited
products compare closely in principal physical to such approaches and offers the flexibility of design
properties (detailed dimensions, etc.) to gelatin application and manufacturing technology to meet
capsules and may be filled on standard capsule-filling the industry’s needs. s
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