2016 清大現代藥用植物導論簡介-曾湘文_20160913v1

Copyright 2016 1Hsiang-Wen Tseng 1Copyright 2016 Hsiang-Wen Tseng

~~

Aprinoa Therapeutics

Director of Preclinical Development

[email protected]

September 13th, 2016

Copyright 2016 2Hsiang-Wen Tseng

Outlines /-/

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CMC () - - GMP-

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From food to botanical drugs

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/(Add-on)

Time

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2009


2010


: IEK (2013)


:1994(Dietary Supplements)

: NHPR (Natural Health Products Regulations;)

: EFSA (European Food Safety Authority, )

: 1991FOSHU (Food for Specified Health Uses;)

1996

1999/2/38/3


2003

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http://www.yihuakang.com/xingongeng.htm

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http://images.google.com.tw/imgres?imgurl=http://pic.nipic.com/2007-11-07/200711711025732_2.jpg&imgrefurl=http://www.nipic.com/show/3/81/e305c1d6fd1a52b4.html&usg=__-sV8l8RW3OCPSMkp7WK_bfMjCnY=&h=837&w=1001&sz=103&hl=zh-TW&start=2&sig2=MSIcfpljTv3HA6BAhMiMMA&um=1&tbnid=FZERGeZeWsK5FM:&tbnh=125&tbnw=149&prev=/images?q=%E4%B8%AD%E5%9C%8B%E4%BF%9D%E5%81%A5%E9%A3%9F%E5%93%81%E6%A8%99%E8%AA%8C&hl=zh-TW&sa=N&um=1&ei=ydE2S4zxIM6GkAXGy-2aBQ


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303 (2016/9/12)


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961224

(Omega-3 acids (EPA+DHA)

(Monacolin K)

2340 (2016/9/1263)


http://consumer.fda.gov.tw/Food/InfoHealthFood.aspx?nodeID=162


---(2010/07/27)

(thioacetamide)

(2010/10/22) (2010/9/10) (2010/10/22) (2010/5/27) (2013.02.05) (2013/10/23) (2014/03/04) (2015/7/9) (2016/4/25)


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http://consumer.fda.gov.tw/Food/Material.aspx?nodeID=160


Global Market For Botanical And Plant-Derived

Drugs To Reach $26.6 Billion In 2017

Source: BCC Research, 2013

Botanical drugs are expected to have a value of $10 million in 2012 and $599 million in 2017,

a CAGR of 126.7%.

All other plant-derived drugs should total $22.1 billion in 2012 and $26.6 billion in 2017, a

CAGR of 3.7%.


Regulation of Botanical Drugs

Product in USA

OTC (over-the-counter) Drug Monograph: The OTC drug review is a three-phase public rulemaking

process resulting in the establishment of standards

(monographs or non-monographs) for an OTC

therapeutic drug category.

These standards provide the marketing conditions for

some OTC drug products including the active

ingredients, labeling, and other general requirements.

For a botanical drug substance to be included in an OTC

monograph, there must be published data establishing a

general recognition of safety and effectiveness,

including the results of adequate and well-controlled

clinical studies.


Regulation of Botanical Drugs

Product in USANDA(new drug application): Under current regulations, if there is no marketing history in the

U.S. or a foreign country for a botanical drug product, if available evidence of safety and effectiveness does not warrant inclusion of the product in an OTC drug monograph, or if the proposed indication would not be appropriate for nonprescription use, the manufacturer must submit an NDA to obtain FDA approval to market the product for the proposed use.

An NDA for a botanical drug could seek approval for either prescription or OTC use, depending on the indication and characteristics of the product and whether it is safe for use outside of the supervision of a practitioner licensed by law to administer it.

An NDA must contain substantial evidence of effectiveness derived from adequate and well-controlled clinical studies, evidence of safety, and adequate chemistry, manufacturing, and controls (CMC) information.

The format of an NDA submission and the requirements for its various sections are set forth in 21 CFR 314 and discussed in several CDER guidances.


1997/4 FDA Guidance on Botanical Products (Draft)

2004/6 Guidance for Industry Botanical Drug Products

2009/3

2012/4

2015/8 Guidance for Industry: Botanical Drug Products

(USA and TW)


FDAs CDERs thinking on

development plans for botanical

drugs submitted in new drug

applications (NDAs).

also presents recommendations

for submitting investigational new

drug applications (INDs) and may

also apply to biologics license

applications (BLAs).

Information on the over-the-

counter (OTC) drug monograph

system for botanical drugs.

FDA defines botanicals as

products that include plant

materials, algae, macroscopic

fungi, and combinations thereof.

Clinical trial: initial (P1/P2) and

expanded (P3)


Approved botanic drugs from USFDA

VeregenTM

(sinecatechins)

FulyzaqTM

(crofelemer)


Veregen

(sinecatechins)

2006/10

MediGene ()

Kunecatechins ()

perianal and genital condyloma.


Fulyzaq (Crofelemer)

2012/12

Salix Pharmacetuticals ()

Crofelemer (Croton Lechleri)

HIV/AIDS(ART)


2016 4 50 4 PG2

PG2

29 19 FDA

36 %

14 28%


&-

(2010) ()

() ()

(2011)

-(2005)

(2013) ()


USFDA

: PHN013PHN033()PHN081

: MSC-2

: SR-T100

: TCM-700

: ON101

: BLI-1301BLI-1005

: JBM-TC4


-1

MCS-2 (Lycopene, Phytoene, Phytofluene): SR-T100(): FDA ON101 (): CFDA FDA MCS-8: 15 MB-6(): BNG-1():

From: 20152016


-2

JBM-TC4 () FDA

BLI-1005 ()

MCS-8 (Solanorubin)

TCM-700C()B TC M-800BB

OB318 ()FDA

()(Idiopathic Thrombocytopenic Purpura, ITP)FDA

From: 20152016


2016/7/18

474318ON-101WH-1ON10111860.334.425.9P=0.004TFDABreakthroughTherapiesTFDA


MCS-2(2016/8/31)

MCS-2FDATFDAMCS-2 MCS-2P0.0134

MCS-21270

MCS-220TFDA


(2016/3/30)

4911SR-T10029SR-T1001610032.397571.83SR-T1004.36SR-T100


Solanum incanum extract (SR-T100) induces human cutaneous squamous

cell carcinoma apoptosis through modulating tumor necrosis factor

receptor signaling pathway

Journal of dermatological science 63(2):83-92 April 2011

Therapeutic effects of SR-T100 gel on UVB-induced papillomas () and MISCCs (, microinvasive squamous cell carcinoma) in hairless mice. All papillomas disappeared within 11 days of topical SR-T100 gel treatment (A and B), and 90% (27/30) of

MISCCs were cleared within 10 weeks of topical SR-T100 gel treatment (AC). In controls, none of the tumors disappeared in mice treated

with the base gel only (A: arrowheads and D), and 88% of them (30/34) became larger (D and E). Remarkably, there were no apparent adverse

effects on the perilesional normal skin, following topical use of both SR-T100 and the base gel. After cure of tumors, only slight atrophy of

skin was noted (A; arrows).


Therapeutic effect of topical SR-T100 gel on human actinic keratosis (AK). A

representative human AK lesion (patient no. 5) was cleared after 16 weeks of topical

treatment with SR-T100 gel. Importantly, SR-T100 gel did not cause damage to the

perilesional normal skin following once daily application for 16 weeks.Journal of dermatological science 63(2):83-92 April 2011


-

From: 2015


2016


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2013

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2008IND

From:


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(in vitro)

cytochrome P450 (CYP450)CYP1A2CYP2C9CYP2C19CYP2D6CYP3A4 (serotonin syndrome)(Ginkgo biloba)warfarin (InternationalNormalized Ratio; INR)

(2013)


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(adequate and well-controlled)(pivotal trial)

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5. (:)

6.

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(2013)


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(dose response study)(surrogate endpoint) (pharmacodynamic endpoint)

(initial studies)Add-on

(2013)


-3

()Phase III study 3 ICH E3ICH E3 (final drug product)

(2013)


(2008)


(2008)

Phase I/II

Phase III

Primary pharmacodynamics

Safety Pharmacology

Single dose toxicity

2*

2*

2


(2008)

Phase I/II

Phase III

Repeated dose toxicity

2A(1)

(2)

(3) 1*

2A(1)

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2B

A

2 2

2 2 2

1 1 1

3 3 3

6 6 6

6 6 9

B

2 1 1

1 3 3

3 6 3

3 6 9


(2008)

Phase I/II

Phase III

In vitro genotoxicity

In vivo genotoxicity

Reproduction toxicity Segment I

Reproduction toxicity Segment II

Reproductiontoxicity Segment III

Carcinogenicity

Local tolerance

Antigenicity

Dependence


100

GCP (good clinical practice, )


-(1)

1.

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3.

1.

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3.

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-(2)

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1. C

2.

3. Domilex

4.

5.

2016 清大現代藥用植物導論 簡介-曾湘文_20160913v1

Health & Medicine

2016 清大現代藥用植物導論簡介-曾湘文_20160913v1