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					                                                                                                    DRUG DELIVERY AND FORMULATION




 The end of gelatine?
 A capsule-forming technology has been developed which not only eliminates
 the use of gelatine, but also paves the way for the development of novel
 pharmaceutical formulations.

 Graham Hind, BioProgress Technology Ltd




O
          n March 20th 1996, the British              (FSA). Gelatine, which is produced by the
          Government announced for the first time     rendering down of animal bones, hooves and
          that bovine spongiform encephalopathy       connective tissue, was specifically mentioned. The
(BSE) might be passed to humans by eating             FSA stated that gelatine should no longer be
beef. This followed the discovery of a new            fed to animals as it was animal-derived and
human form of Creutzfeld-Jakob disease (CJD),         contravened the FSA recommendations that
from which seven people under the age of 42           intra-species recycling (cannibalism) should be
had already died. Coincidentally, six days later on   totally banned. This ban would include vitamin
March 26th 1996, BioProgress Technology Ltd           supplements routinely given to animals, which
filed the first of seven patents for a new            were contained in or coated with gelatine.
animal-free soft capsule process, the XGel ™             The evidence concerning the safety of gelatine is
system. This new technology was designed to           currently circumstantial. However, even the remote     This new
replace the traditional gelatine process by which     possibility that gelatine could - in the future - be
soft capsules had been made for over sixty years.     proven to be a health problem has prompted all the     technology was
    In the US, a committee of the Food and Drugs      major global pharmaceutical companies to actively      designed to
Administration (FDA) recommended that gelatine        seek an alternative to gelatine and animal-derived     replace the
should be removed from the “generally regarded        products for capsules and tablet-coating.
as safe” (GRAS) list. Gelatine was in the news                                                               traditional
                                                      An animal-free system
again as recently as October 2000, following the                                                             gelatine process
publication of a review of BSE-related safety         Development of the animal-free XGel™ system by
measures by the new UK Foods Standards Agency         BioProgress was not prompted by the BSE crisis
                                                                                                             by which soft
                                                                                                             capsules had
                                                                                                             been made for
                                                                                                             over sixty years




Figure 1.     Ingestible soft capsules.


Innovations in Pharmaceutical Technology                                                                                     117
DRUG DELIVERY AND FORMULATION




                          Figure 2.    Non-ingestible PVA capsules.



The system was           and, although welcomed by vegetarian groups,        come from an unexpected source; this is true in
                         it should not be seen as a niche animal-free        the case of the XGel™ encapsulation system.
 conceived and           alternative aimed at vegetarians and ethnic and     BioProgress Technology Ltd was formed by a
  designed as a          religious groups. The system was conceived and      group of material scientists in Cambridge in 1991,
     lower cost,         designed as a lower cost, faster and more           funded initially by a UK government Special
                         flexible capsule-production system - enabling the   Projects Under Research (SPUR) grant. The grant
      faster and         development of innovative new products which        was awarded to BioProgress to develop new
   more flexible         were previously not technically possible given
                                                                             water-soluble and biodegradable films to replace
                         the limitations of the now sixty-five year old
        capsule-         gelatine process.                                   traditional polythene films widely used in
                                                                             disposable baby nappies and feminine hygiene
     production              Sometimes the technical breakthroughs which
                                                                             products. The design goal was to create new
                         have the potential to revolutionise an industry
       system ...                                                            environmentally-friendly products which would
                                                                             function normally, but which would biodegrade
                                                                             rather than remain indefinitely in landfill. In
                                                                             1992, the BBC Tomorrows World TV programme
                                                                             featured the world’s first flushable baby
                                                                             nappy developed by BioProgress, and flushable
                                                                             biodegradable feminine hygiene products (using
                                                                             this technology under licence from BioProgress)
                                                                             are now on sale in the US and Canada.
                                                                             BioProgress was awarded its first UK government
                                                                             Millennium Design award for this technology.
                                                                                 By 1996, BioProgress had accumulated an
                                                                             extensive and unique knowledge-base of the
                                                                             characteristics and behaviour of water-soluble
                                                                             films in an extensive range of applications. The
                                                                             company was set a challenge to produce an
                                                                             alternative to gelatine for the encapsulation of
                                                                             cosmetic bath oils by a retailer who was concerned
                                                                             that selling gelatine bath-beads was not compatible
       Figure 3.   Septum ingestible capsule.                                with the company’s non-animal testing and

118                                                                                          Innovations in Pharmaceutical Technology
DRUG DELIVERY AND FORMULATION




          Figure 4.   Enrobed tablet.



                         generally animal-friendly stance. By 1998,            the rotary die capsule-forming head. Once a batch
                         development of XGel™ - the world’s first non-         of gelatine is ready, it must be used as it cannot
                         animal-based soft capsule system - was complete;      be stored. The gelatine ribbon width is limited
                         BioProgress was awarded its second Millennium         to around only 25cm. Wider widths produce
                         Design Award for XGel™. This non-ingestible           inconsistencies in the thickness of the ribbon; this
                         encapsulation version of the system uses a            causes more reject capsules - negating any extra
                         proprietary formulation of polyvinyl alcohol film     production advantages gained from the wider
                         (PVA) (Figure 2). This system is now being further    ribbon width. This limitation on ribbon-width has
                         developed in collaboration with a number of multi-    a direct effect on the hourly capsule production
                         national companies to produce capsules - which        outputs possible with the gelatine process.
                         can be as large as 35mm in diameter - for                 The XGel ™ system uses two rolls of
                         the single dose delivery of a wide range of           pre-formed proprietary formulation cellulose film;
                         new consumer products. The ability to engineer        this can be stored virtually indefinitely so the
                         specific dissolution characteristics - even in cold   system can be switched on and off as required.
                         water - makes the system revolutionary.               There is no theoretical limit to the film width
                                                                               but, for example, at two metres wide and running
                         Pharmaceutical applications
                                                                               at the same speed as a gelatine rotary die machine,
   The ability to        Having successfully developed an alternative to       the system can produce eight times the hourly
engineer specific        gelatine capsules for non-edible applications, the    capsule output of a gelatine machine.
                         company then set about designing a version of the     Furthermore, an XGel™ machine can be run at a
      dissolution        system to replace gelatine for dietary supplements    faster rate than a gelatine machine - creating even
 characteristics -       and pharmaceutical products. For this version of      greater output gains. The cellulose film is strong
                         the XGel™ system, it was decided to develop a         and so can be used at a fraction of the thickness
    even in cold         film made from natural renewable plant-based          of a gelatine ribbon. Also, considerably less
  water - makes          materials which would be acceptable to all those      material is used per capsule - delivering a further
     the system          who objected to the animal origins of gelatine. The   cost advantage.
                         film developed is cellulose-based and is fully            As the gelatine process is wet, powders cannot
   revolutionary         approved by the FDA for pharmaceutical use. The       be encapsulated; furthermore, after forming,
                         characteristics of the film were different from PVA   gelatine capsules need to be dried in expensive
                         and thus necessitated a re-design of the XGel™        air-conditioned facilities - sometimes for several
                         capsule-forming mechanism.                            days. By contrast, XGel™ capsules are dry and
                             The best way to illustrate the truly innovative   can be packed immediately. The elimination of
                         features of the XGel™ system would be to              pre-mixing and post-encapsulation drying removes
                         compare it with the traditional gelatine capsule      some of the expensive production stages needed
                         process. Gelatine is heated and mixed with            in the gelatine process. The lack of need for this
                         other materials until it is at exactly the correct    support infrastructure makes XGel™ a low-cost
                         consistency; it is then rapidly cooled and formed     and compact system, with the ability to add
                         into ribbons. The gelatine ribbon is presented to     further systems and capacity - at a much lower

120                                                                                            Innovations in Pharmaceutical Technology
                                                                                                          DRUG DELIVERY AND FORMULATION




capital investment than would be required to               is a dry process, it can replace solvent tablet
expand capacity with a gelatine process.                   spray-coating (with its attendant expensive safety
    The new system makes it viable for companies           precautions and solvent recovery). The new
to invest in in-house soft capsule production,             tablet-enrobing system is currently completing
rather than buying-in gelatine capsules from a toll        the evaluation stage with one of the world’s
manufacturer. Toll manufacturing has tended to             leading pharmaceutical companies, and it is
become the norm for the gelatine process, due to           planned that the system will be generally available
its high capital cost and the fact that it is a complex    during 2001. A miniature laboratory version of
and specialised process. Also, the performance             the system is also available to enable stability-
characteristics of gelatine as a material are relatively   testing and clinical trial production on a small scale
fixed. With more than thirty different film                for new pharmaceutical products.
formulations available and any film thickness
possible, XGel™ capsules can be designed to
dissolve almost instantly in the mouth (without
the chewy characteristics of gelatine) - or, indeed,
at any time or site in the body by manipulation of
the film formulation to create specific oxygen
barrier or dissolution characteristics. After eighteen                                                              This technology
months of thorough evaluation, Peter Black                                                                          will facilitate the
Healthcare (a leading UK manufacturer of                                                                            development of
vitamins, minerals and supplements) made the
decision to license the XGel™ technology and                                                                        exciting new
order systems for its production facilities.                                                                        pharmaceutical
A two-halved capsule                                                                                                products
The most revolutionary feature of the new system                                                                    not previously
is the “septum” capsule (Figure 3). As the two                                                                      possible
halves of the capsule are formed, a third film
down the centre of the capsule creates two
separated capsule halves in the same capsule; this
enables two incompatible active ingredients to
be filled in the same capsule. By altering the
dissolution characteristics of the two outside films,
it is possible to deliver the two fills in the same
capsule at different times or sites in the body.                                     Graham Hind is Managing
The “septum” capsule can deliver two liquids, or                                     Director of BioProgress
two powders, or a liquid and a powder in any                                         Technology Ltd. He has
combination. This technology will facilitate the                                     more than twenty-five years’
development of exciting new pharmaceutical                                           experience in managing
products not previously possible. The “septum”                                       and expanding scientific
technology also provides an animal-free tamper-            nutrition companies. In the mid-1970s and 80s, he
proof alternative to the traditional two-part              was responsible for establishing the Milupa baby
gelatine capsule widely used for pharmaceuticals.          food brand in the UK - from introduction to brand
Tablet enrobing                                            leadership. In the early 1990s, he joined Royal
                                                           Numico - forming and heading up their new division
Gelatine is also used to coat tablets through a dip-       for dietary supplements and OTC medicines. In the
ping process. This is a relatively slow, wet process       mid-1990s, he founded DHA Nutrition Ltd, a
requiring a tablet-drying stage. BioProgress has           company involved in developing functional foods and
developed a new tablet-enrobing version of
                                                           nutraceuticals using long-chain polyunsaturated fatty
the XGel™ system. The key to this was the
                                                           acids. In 1998, DHA Nutrition was acquired by
development of new extremely high-gloss cellulose
coloured films. Tablets are shrink-wrapped in any          BioProgress Technology International Inc, and Mr
combination of brightly coloured film - this can           Hind became a Director of the US holding company
also be pre-printed for product identity and               with responsibility for encapsulation technology
branding purposes (Figure 4). This not only has            licensing outside of North America; he also became
the potential to replace gelatine tablet-coating, but      Managing Director of the UK subsidiary, BioProgress
is cheaper and - being a continuous rather than            Technology Ltd, where he is responsible for research
a batch process - is faster than traditional               and development. Graham Hind can be contacted at:
accelacota-type spray-coating. In addition, as it          GrahamHind@aol.com

Innovations in Pharmaceutical Technology                                                                                            121

				
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