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  ??? ???? ??? ???? ???, ????? ???? ??? ??? ?? ????
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  ???
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lt ? ? gt

• 1958??? NCI ???? 1,550?, 3,390?? ??? 114,000?
  ???? ??? ??? ?? ????. ? ????? ?? ?? ???? ?? ?? ??
  7,000??? 23,000 ?? ???? ?? AIDS ????? ?? ?? ?? ?.
• - Vincristine, vinblastine, leurosine,
  leurosidine ? ??? ???? ??
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  ?? ??
• 1980?? ? ???? ??? ??? teprotide? lead ???? ??
  ACE??? ??
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  ?.
• Topotecan, N',N'-bis(ethyl)norspermine,
  Ellipticine ??? ?? ???? ????? ???. -by NCDDG
  (National Cooperative Natural Products Drug
  Discovery Groups)

12
????? ???? ?? -?? ??
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  ?? ???.
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  Pool? ??
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????? ???? ?? -?? ??
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  artemisinin (Quinine
• ??? ????) ??
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  ???? ???
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lt ? ? gt

• 1990? ????? ???? ??, 1991? Human Science ???? ??,
  1992? Pharma Dream ???? ? ??? ??? ????? ?????
  ???? ??
• ?? ???, ???? ? ??????? ???? ?? ?? ???? ?? ?

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?? ??? ?? ? ????? ??? ?? ?? ?? (I)
15
?? ??? ?? ? ????? ??? ?? ?? ?? (II)
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?? ??? ?? ?? ??

• ????? ?? ?? ? Infra ??
• - ????? ??? ?????, ?? ???? ? ??, GMP ?? ????
  ??
• ??? ??? ??? ?? ????? ?? ??? ???.
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  ??
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  0.07? ??
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  ???? ???? ??
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?? ????? ????? ?? ? ???? ??
(2003?)
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(2001??, ???)
??? ???? ????? ?? ? ?? ????
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??? ????? ??? ???? ??
20
GINNEXIN

• ?? ???(Schwabe)?? ?? ??? ??? ???? ???? ??? ?? ??
  (EGb761)
• ???? - ???? ??? ?? ??
• ??? ?? ?? ?? - ?? ??????? ???? ??? ???? ????? ?
  ?? ??? ??? ?? ?? ?? ????
• ?? ?? ??? ?? ?? ?? ??

21
JOINS - New herbal materials for anti-arthritis
Code No.
SKI 306X
Brand name
SK pharma (Korea) Joins Chalmers Dale
(Australia) Cararthron
22
Development of Joins
JOINS
Searching by philosophy of Oriental Medicine
600 -gt 53 pharmacological active herbs
Screening through modern science technology
Selection 3 herbs optimization
Joins New approach for Arthritis
23
History
JOINS
Event
date

• Oriental Medicinal Philosophy, Screening

1993. 1. 1994. 12.

• Pre-clinical Study

1995. 1. 1997. 8.
1997. 12.

• IND filing

• Phase II Clinical Study

1998. 1. 1999. 11

• Phase III Clinical Study

1999. 12. 2001. 3

• NDA

2001. 7.
Korea
2002. 2.

• Launch

• Soft launch
• New South Wales Guild Pharmacy Fair

Australia
2002. 6.

• Major Launch
• Natural Healthcare Expo 2002

2002. 9
24
Composition of Joins
JOINS
Prunella vulgaris
Trichosanthes kirilowii
Joins
Clematis mansshurica
Blood circulation anti - oxidation
Anti - inflammation Analgesic effect
Cartilage protection
Immune - modulation
25
Extraction scheme of active materials
JOINS
26
Preclinical study of Joins - Pharmacology
JOINS
Multi-functions
Anti-inflammation
Relieve Pain Inhibit chronic inflammation
process
Inhibit inflammation by immune response (eg. RA)
Immune -modulation
Prevent ischemic stress of joint
Blood circulation
Cartilage protection
Prevent cartilage degradation
27
JOINS Pharmacology
1. Effect on Inflammation Analgesic Process
5-Lipoxygenase activity
Cyclooxygenases expression
Joins
Analgesic
Anti-inflammation
iNO synthase activity
Human TNF-? expression
Joins has potent efficacy through
multi - mechanisms
28
JOINS Pharmacology
2.Effect on Immuno-modulation
Suppression of Lymphocyte Proliferation by
Inflammation mediator - B-Lymphocyte -
T-Lymphocyte
No effect on normal lymphocyte
Joins is Effective on Inflammation
through Immunological Response
29
JOINS Pharmacology
3. Effect on Blood Circulation
Free-Radical Scavenging
Promotion of Fibrinolytic Activity
Inhibition of Platelet Aggregation
Joins activates blood circulation
30
JOINS Pharmacology
4. Cartilage Protective effects
Inflammation, Immune Response

• Various enzymes expression
• (MMPs, aggrecanases ...)
• Cytokine increase (IL-1)
• Oxygen radical generation

Joins
Joins
Articular Cartilage Erosion
Exacerbation of Pain, Function Loss
Joins prevents articular cartilage degradation
31
Preclinical study of Joins - Toxicology
JOINS
Acute toxicity LD50 gt 5g/Kg Subacute
toxicology (4 weeks) - Dose 0.0 3.0
g/kg/day - Dead animal not observed in male
/ female - All are in the normal range -
Histopathology No significant
difference Chronic toxicology (6 Months) - Under
Going
32
JOINS Clinical studies
Clinical studies - Phase II
Objective
To evaluate the effect of Joins, a new herbal
anti-arthritic agent, in patients with
osteoarthritis of the knee a double-blind
placebo controlled study (4wks)
Results
Treatment groups
Placebo
200mg
400mg
600mg
Primary end point, 100mm Visual Analogue Scale
Mean difference
-7.515.5
-23.616.3
-22.014.0
-29.817.4
Secondary end point
33
JOINS Clinical studies
Clinical studies - Phase II
Drug-related adverse events
30
26.1
20
21.7
20.8
10
13
0
Placebo
200mg
400mg
600mg
The most suitable dosage of Joins is 200 mg t.i.d
34
JOINS Clinical studies
Clinical studies - Phase III
Objective
A four-week, randomized, double-blind trial of
the efficacy and safety of Joins, a novel herbal
anti-arthritic agent versus diclofenac (Vortagen.
S.R) in osteoarthritis of the knee(N249) 5
Hospitals 6 Researchers for the clinical study
Results
Results of the efficacy assessments
- 100mm Visual Analogue Scale
35
JOINS Clinical studies
Clinical studies - Phase III
Results of the efficacy assessments - Opinion of
therapeutic efficacy
Drug-related adverse events - Comparison between
Joins- diclofenac-treated group
Low incidence of G.I troubles and others
Joins (N125) 24case (19.2) diclofenac
(N124) 46case (37.1)
36
Clinical studies
JOINS

• In phase II clinical study
• Optimal dose is 200mg t.i.d.
• In phase III clinical study
• The equi-potent to NSAID drug (diclofenac)
• Low incidence of G.I troubles and others
• Good tolerability for long term administration

37
Patent Status
JOINS
Title
Process of extracting and purifying
biological effective ingredient from combined
medical plants and their extract composition
Basic Korean Patent Registered No.
180,567(2/12/98)
Country
Code
Application No.
Japan Canada USA Europe
JP CA US EP
250611/96(20/09/96) 2,185,983(19/09/96) 08/716,058
(19/09/96) 96115039.8(19/09/96)
Registered has been received Registered been
paid.
Including Italy, Germany, France
Title
Herbal drug composition for cartilage protection
Basic Korean Application 2001-27231(11/05/2001)
PCT Application PCT/KR02-00010
(04/01/2002) Now, applied to other countries
(include AU) for a patent based on above PCT
Application.
38
LJI - anti-inflammatory analgesic injection
Target herbal medicine - L. japonica
Traditional use diuretics,
latent-heat-clearing agent, antipyretics,
antidote,
anti-inflammatory agent Folk use for the
treatments of upper respiratory tract infections,
tonsillitis, diabetes
mellitus and rheumatoid arthritis
39
Progress of the development
LJI

• Select 50 species of herbs from old books to
  screen for their anti-inflammatory
• and analgesic activities
• Co-work with Kangwon Natl. Univ., Andong Natl.
  Univ., Seoul Natl. Univ. and
• Yeungnam Univ.
• ? The development start of anti-inflammatory
  and analgesic drug for p.o.
• administration (93. 3)
• Giving up the development because of the very
  high manufacturing cost (95. 5)
• The change of the development strategies p.o.
  gt i.v. or i.m. formulation (97. 11)
• This project was selected as the one of the MOHW
  projects, supporting business
• for the new drug development (01. 6).
• The selection of active fraction and the
  development of purification process (02. 3)
• Under pre-clinical study/preliminary arrangement
  for IND filing (02. 12)

40
Extraction Purification
LJI
Process
The stems of L. Japonica
Extraction with DW
Fractionation with DW- saturated n-BuOH
Product (yield 0.28)
2nd purification
Evaporation of n-BuOH fraction in vacuo
The purified material of liquid phase
Drying
1st purification
Powder
Water soluble part
41
LJI Extraction Purification
Extraction Purification
HPLC chromatogram of final material
SKSW (ca 30)
SKLO (ca 20)
254 nm
42
Pharmacology
LJI
Anti-inflammatory effects
- Croton oil - induced ear edema (iv, im, po) -
Arachidonic acid - induced ear edema (iv, im, po)
43
LJI Pharmacology
Pharmacology
Analgesic effects
Post operative pain test (iv)
Acetic acid - induced writhing (iv, im) Post
operative pain test (i.v.) Randall and Sellitos
test (iv)
Acetic acid - induced writhing (iv)
Randall and Sellitos test (iv)
44
LJI Pharmacology
Pharmacology
Other effect
Passive cutaneous anaphylaxis (PCA) test (i.v.)



Control
Prednisolone (p.o.)
SKLJI
(?/?)
100
2 10 25
45
LJI Pharmacology
Pharmacology
Mechanism Studies

• Inhibitory effects on 5-lipoxygenase activity in
  A23187-stimulated human whole blood
• Inhibition of human TNF-? release from
  LPS-stimulated human whole blood
• Anti-oxidative effect on rat washed platelets
  (WP)
• Inhibitory effect on COX-2 expression at COX-2
  stable RAW264.7 cell line
• Inhibitory effect on iNOs expression in RAW264.7
  cell line

46
Safety Studies
LJI

• ????? ??? ?? (Irwin test)
• ?????? ??? ??
• Mouse?? acetic acid? ??? ????
• Mouse?? thiopental? ??? ????
• Rat?? ?????? ??? ??
• Mouse?? ??? ??? ??
• Mouse?? pentylenetetrazole? ???
• ?????
• Mouse?? ????? ??? ??

• ?????? ????? ??? ??
• ??, ???, ??, ???, ???, ???
• ????? ??? ??
• ????? ??? ??
• ????? ??? ??
• Mouse?? charcoal ???? ???
• ??
• Rat?? ????? ??? ??
• ???? ??? ??
• ???? ? ????? ??? ??

47
Toxicological studies
LJI
?? ??
?? (mg/kg, i.v.)
?? ???

• ???? ????

889, 1333, 2000 63, 250, 1000
Rat dog

• ???? ?? ?? (4?)
• ???? ?? (Antigenicity test)
• ????? (?????? ??)
• ???? ?????? ??
• ???? ??
• ?????? ?? (Ames test)
• ????? ??
• ????
• ???? ??
• ???? ?? ??
• ???? ?? ??
• ?? ? ???? ??
• ??? ? ??? ????
• ?? ?? ?? ? ??????
• ??? ????

50, 200, 800 25, 100, 400 0.83, 8.3 FCA 0.83,
8.3 FCA 0.062 5 mg/ml 0.137 5 mg/ml 400,
800, 1600 25 mg/ml 25 mg/ml 50, 200, 800 50,
200, 800 25, 100, 400
Rat Dog Guinea pig Guinea pig in vitro in
vitro mouse Rabbit Rabbit Rat Rat Rat, Rabbit
48
Formulation studies
LJI

• ?? ? ???? ??
• - ??, ????, pH, ?????, ??????, ??????,
  ??????,
• ???????, ????, ????
• ?? ??? ?? (3??)
• - ?????? (25?, 60RH), ???? (40?, 75RH)
• ??? ??? ?? (3??)
• - ?????? (25?, 60RH), ???? (40?, 75RH)
• ?? ? ???? ??
• - ?? ? ??? ?????, ????, ????, pH, ???, ?????,
  
• ??????, ???? ??? ? ??
• - TLC ? HPLC ???? ??

49
Further studies
LJI

• Search more Active Ingredients
• Do More Mechanism studies
• Search Target diseases
• Do Clinical studies