SCHEDULE C
DEVELOPMENT PROGRAM FOR NEUTRACEUTICAL AND COSMETIC AGENTS.
MAJOR ITEMS
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SCALE-UP
Bulk isolation and purification for "batch" preparations
Time 2 months ( 2 weeks)
a) Along the way to full scale production pilot batches will be QA'd and
combined for immediate use in all tests
b) Target is for 250 g batch sizes
ARTHRITIS TRIALS
Time 6 months
This includes: 1) Ethics Committee approval (application in by 29/1/99)
2) Re-establishing model (active and passive)
3) Delivery and dose-finding studies including
i) Gavage
ii) Drinking water
iii) Food
iv) confirmation by mini-osmotic pump delivery
SKIN TRIALS
Time 6 - 8 months
This includes: 1) Formulation preparations (negotiations now going)
2) Evaluate dermal delivery formulations
3) Establishing a model for quick delivery assessment
4) Establish a wrinkle model and test materials
EXPECTED TIMING
0-3 MONTHS
PREPARATION OF BATCH MATERIAL FOR ALL SUBSEQUENT TESTING.
A large scale preparation of material has been produced and purified using
a gel filtration procedure. A quantity of approximately 50 grams has been
purified but the gel filtration procedure is still inefficient and 50 grams
is still not sufficient for the oral availability studies to be commenced
(and completed). A new and hopefully more efficient gel filtration column
is currently being installed in the laboratory for this purpose.
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PRODUCE FORMULATIONS FOR SKIN TESTING
Several skin formulations have been assessed in the rat model and to date
none of these formulations have had an effect equivalent to the intradermal
injection of material. The skin formulations tested to date have included
ethanol, DMSO and oleic acid. A consultant specialist skin formulation
company has been approached to provide alternative formulations for
testing.
COMMENCE TRIALS IN ANIMAL MODELS OF RHEUMATOID ARTHRITIS
An animal model of rheumatoid arthritis has been established in rats. The
model is called the adjuvant arthritis model and is the result of adjuvant
treatment of rats which causes joint swelling and inflammation within three
weeks. Lymphocytes from adjuvant treated rats are transferred to naive rats
and these rats develop joint signs within two weeks. The severity of the
arthritis is assessed by measuring the thickness of the ankle joints daily
and by histological examination of the joints after two weeks. Using this
model it has been found that the Praxis agents consistently and
significantly reduce the severity of the arthritis. Several agents have
been tested and shown to work (see May, 2000 research report) in the model.
The agents were administered by infusion pump into the subcutaneous tissue
over a two week period. Now that the model is established and we have shown
the efficacy of the agents under development it is awaiting sufficient
material to test the oral effectiveness which requires the agents to be
administered in the drinking water. It is hoped that sufficient will be
available start this in 3 weeks time.
3-6 MONTHS
TEST SKIN FORMULATIONS FOR PENETRATION AND EFFECT
As noted above several skin formulations have been produced and tested for
their effectiveness in remodeling the skin of rats. No formulations have
been as effective as an intradermal injection. Penetration is to be
assessed in the future using fluorescently labeled material which can be
assessed for penetration using standard immunohistology procedures.
COMPLETE RHEUMATOID ARTHRITIS ANIMAL STUDIES
As noted these studies cannot commence until sufficient material has
finally been purified (100 grams).
6-9 MONTHS
BEGIN SKIN TOXICITY STUDIES
Preliminary skin toxicity studies have been done in rats. These studies
were of two weeks duration. No adverse effects were observed by visual
inspection or by histological examination. More extended studies are to be
performed in the next three months including UV exposure effects.
FILE SKIN COSMETIC PATENT (MATERIAL AND FORMULATION COVERAGE)
A provisional patent has been drafted but not yet filed. The patent covers
the agents structure and the use for management of wrinkles by
administration topically and by injection. Finalization of the patent and
filing is expected to be completed in 2-3 weeks.
9-12 MONTHS
COMPLETE SKIN TOXICITY STUDIES
See comments above
COMMENCE ANIMAL WRINKLE MODEL STUDIES
A specialized UV irradiation system is currently being installed in the
animal facility to commence the mouse skin wrinkles studies. The unusual
strain of mice needed for these studies (hairless mouse) has been imported
into the animal facility and bred up to sufficient numbers to commence the
studies. It is anticipated that the lighting system should be in place in a
few weeks and that the wrinkling studies will commence immediately it is in
place.
12 MONTHS-
Complete wrinkle model studies
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