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Kuliah Farmasi Industri 2

Drug Development

Riset/Pengembangan Obat
Mengapa perlu : Belum ada obatnya : HIV / DBD/AVF Mencari yg lebih ideal : ampuh/aman/terjangkau/praktis,dlsb . Mis : Obat TBC , malaria Perluasan product range Inovasi bentuk sediaan

Faktor2 penting

Tingkat kebutuhan : Data demografis, epidemiologis, disease burden Potensi ekonomi : volume, segmen pasar Keterjangkauan : harga vs segmen pasar Potensi pasar jangka panjang : perkiraan siklus hidup produk

Tantangan pengembangan obat

Profil produk yang ideal Biaya Uji klinis Aspek2 regulasi

Global Impact of malaria*

Endemic countries : 101 Deaths/year : 1.2 million Clinical cases/year : 300 500 million

* WHO report 2003

The Pharmaceutical Industry and New Drug Development

US pharmaceutical industry leads the world in drug production and sales:77 billion in 1995

Invests more of its revenue in R&D than any other industry In the R&D lifecycle, prominent role of clinical trials

R & D Lifecycle

Discovery or creation of a new compound Devise methods to synthesize compounds reliably Screen the biological activity in animal and in vitro models Conduct tests to describe animal pharmacology, toxicology,and pharmacokinetics Compound that show promise in preclinical testing advances to clinical development Determine systemically safety, tolerability and efficacy in humans

R & D Lifecycle

IND (Notice of claimed exemption for a new drug) application to FDA IND documents consist of biology,chemistry and toxicology determined to date for new drug

Describes in detail proposed clinical studies sponsor will conduct to establish safety and efficacy for human use
For approval to market, FDA requires sponsor to conduct series of studies to document safety and therapeutic value 3 phases of Clinical Trials

Phase 1
Clinical Pharmacology

Initial introduction into human subjects after appropriate preclinical safety studies Almost always inpatient studies with healthy volunteers (cancer and rare diseases exception) Emphasis on safety not effectiveness Subject tolerance and adverse clinical effects,lab effects observed as drug dosage is increased in amount and frequency Studies may include drug metabolism,PK,mechanism of action Estimates dose to be used in subsequent trials

Phase II

Controlled Clinical Trials

Evaluate the effectiveness of the new drug in a small number of patients with the target disease Better define the dose and regimen Examine short term adverse events or other risk Objectively measure drug effectiveness Chiefly in outpatient patients Most trials have placebo control group(exception:oral contraceptives,most anti infectives,cancer chemotherapy) Efficacy,dose regimen,safety profile reasonably well defined by end of phase 11

Phase III
Expanded clinical trials

Expand phase 11 trials by enrolling large number of patients patients to evaluate effectiveness and further safety profile Large scale multicentre trials Studies in special population: children,elderly,subjects in impaired organ functions Model future presciption ie define drugs effectiveness in routine and special populations,provide fuller definition of common side effects and uncommon adverse events Benefit to risk relationship Cost effectiveness (pharmacoeconomics) Impact on quality of life Interactions with other drugs Develop labeling for marketing presciption

The Marketing application

NDA ( New drug application)

Sponsors request for FDA approval to market Submitted after clinical studies completed and sponsor satisfied new drug demonstrated to safe and effective for intended use Documents: Overall summary of project Manufacturing and control data Reports from all preclinical studies Clinical summary of entire development program All protocols,CRF,related raw data Summaries of each clinical study Published and unpublished reports on drug Proposed package insert

Phase IV
Post marketing studies

Performed after new drug approval Define efficacy/safety for unapproved indications Compare efficacy/safety vs marketed competitors Cost effectiveness of new drug Define new dosing regimens

Typical times to develop a new drug

Stage of development
Discovery to IND Phase I

Range(yrs) Average
0.5-2.5 0.5-1.5 1.5 1.0

Phase II
Phase III NDA,FDA review & approval

1.0-5.0 1.0-5.0

3.0 2.0




Drug Development : high risk ,low yield

5,000-10,000 synthesized compounds 1000 screened 100 preclinically tested 10 clinically tested 1-2 marketed

Rancangan Produk
1. Tahap2 Formulasi : Preformulasi Formulasi (Skala lab) Tahap evaluasi stabilitas Scale up 2. Sifat2 bahan : Bahan berkhasiat Bahan penolong Wadah Kemasan 3. Bentuk sediaan



product formulation 1-2 years Local registration - 1 year WHO pre-qualification 1-2 years EXPENSIVE Materials for experimental pilot batches. Biostudies especially for FDCs Retention of appropriate technical skills.

PRODUCT DEVELOPMENT PROCESS RISKY No guarantees for success Domestic markets too small for viability while pursuing WHO pre-qualification. If successful can realistically expect return in 5 years.


THE TRIAD/AXIS OF SUCCESS GVNT +DRA & WHO + COMPANY STRONG COMPLEMENTARY INDUSTRY especially for packaging and Engineering BUILDING STRONG CHEMICAL MANUFACTURING INDUSTRY FOR ARV APIs. MIGRATION OF SKILLS over 200 Pcists to UK in one year (over 7 years national output of Pcists)



Plant Based Drugs and Medicines

Drug/Chemical Acetyldigoxin Adoniside Action/Clinical Use Cardiotonic Cardiotonic Plant Source Digitalis lanata Adonis vernalis

Aesculetin Agrimophol Ajmalicine Allantoin Allyl isothiocyanate Anabesine Andrographolide Anisodamine

Anti-dysentery Anthelmintic Circulatory Disorders Vulnerary Rubefacient Skeletal muscle relaxant Baccillary dysentery Anticholinergic

Aesculus hippocastanum
Frazinus rhychophylla Agrimonia supatoria Rauvolfia sepentina Several plants Brassica nigra Anabasis sphylla Andrographis paniculata Anisodus tanguticus

Plant Based Drugs and Medicines

Drug/Chemical Anisodine Action/Clinical Use Anticholinergic Plant Source Anisodus tanguticus

Asiaticoside Atropine Benzyl benzoate Berberine Bergenin Betulinic acid

Vulnerary Anticholinergic Scabicide Bacillary dysentery Antitussive Anticancerous

Areca catechu
Centella asiatica Atropa belladonna Several plants Berberis vulgaris Ardisia japonica Betula alba

Bromelain Caffeine

Antipyretic, analgesic, antiinflammatory

Anti-inflammatory, proteolytic CNS stimulant

Several plants
Ananas comosus Camellia sinensis

Plant Based Drugs and Medicines

Drug/Chemical Camphor Camptothecin (+)-Catechin Chymopapain Cissampeline Action/Clinical Use Rubefacient Anticancerous Haemostatic Proteolytic, mucolytic Skeletal muscle relaxant Plant Source Cinnamomum camphora Camptotheca acuminata Potentilla fragarioides Carica papaya Cissampelos pareira

Codeine Colchiceine amide Colchicine Convallatoxin Curcumin

Local anaesthetic
Analgesic, antitussive Antitumor agent Antitumor agent, antigout Cardiotonic Choleretic

Erythroxylum coca
Papaver somniferum Colchicum autumnale Colchicum autumnale Convallaria majalis Curcuma longa

Plant Based Drugs and Medicines

Drug/Chemical Cynarin Danthron Action/Clinical Use Choleretic Laxative Plant Source Cynara scolymus Cassia species

Deserpidine Deslanoside L-Dopa Digitalin Digitoxin

Antitumor agent
Antihypertensive, tranquillizer Cardiotonic Anti-parkinsonism Cardiotonic Cardiotonic

Colchicum autumnale
Rauvolfia canescens Digitalis lanata Mucuna sp Digitalis purpurea Digitalis purpurea

Emetine Ephedrine

Amoebicide, emetic

Digitalis purpurea
Cephaelis ipecacuanha

Plant Based Drugs and Medicines

Drug/Chemical Etoposide Galanthamine Action/Clinical Use Antitumor agent Cholinesterase inhibitor Plant Source Podophyllum peltatum Lycoris squamigera

Glaucarubin Glaucine Glasiovine

Amoebicide Antitussive Antidepressant

Digitalis purpurea
Simarouba glauca Glaucium flavum Octea glaziovii

Gossypol Hemsleyadin Hesperidin

Sweetener, Addison's disease

Male contraceptive Bacillary dysentery Capillary fragility

Glycyrrhiza glabra
Gossypium species Hemsleya amabilis Citrus species

Plant Based Drugs and Medicines

Drug/Chemical Hyoscyamine Irinotecan Kaibic acud Kawain Kheltin Lanatosides A, B, C Lapachol Action/Clinical Use Anticholinergic Anticancer, antitumor agent Ascaricide Tranquillizer Bronchodilator Cardiotonic Anticancer, antitumor Plant Source Hyoscyamus niger Camptotheca acuminata Digenea simplex Piper methysticum Ammi visaga Digitalis lanata Tabebuia sp.

Menthol Methyl salicylate

Smoking deterrant, respiratory stimulant

Rubefacient Rubefacient

Lobelia inflata
Mentha species Gaultheria procumbens

Plant Based Drugs and Medicines

Drug/Chemical Monocrotaline Morphine Neoandrographolide Nicotine Nordihydroguaiaretic acid Noscapine Action/Clinical Use Antitumor agent (topical) Analgesic Dysentery Insecticide Antioxidant Antitussive Plant Source Crotalaria sessiliflora Papaver somniferum Andrographis paniculata Nicotiana tabacum Larrea divaricata Papaver somniferum

Pachycarpine Palmatine Papain

Oxytocic Antipyretic, detoxicant Proteolytic, mucolytic

Strophanthus gratus
Sophora pschycarpa Coptis japonica Carica papaya

Plant Based Drugs and Medicines

Drug/Chemical Action/Clinical Use Plant Source

Physostigmine Picrotoxin Pilocarpine

Cholinesterase Inhibitor Analeptic Parasympathomimetic

Hydrangea macrophylla
Physostigma venenosum Anamirta cocculus Pilocarpus jaborandi

Podophyllotoxin Protoveratrines A, B Pseudoephredrine* Pseudoephedrine, norQuinidine

Antitumor anticancer agent Antihypertensives Sympathomimetic Sympathomimetic Antiarrhythmic

Several plants
Podophyllum peltatum Veratrum album Ephedra sinica Ephedra sinica Cinchona ledgeriana

Plant Based Drugs and Medicines

Drug/Chemical Qulsqualic acid Rescinnamine Reserpine Rhomitoxin Rorifone Rotenone Rotundine Rutin Action/Clinical Use Anthelmintic Antihypertensive, tranquillizer Antihypertensive, tranquillizer Antihypertensive, tranquillizer Antitussive Piscicide, Insecticide Analagesic, sedative, traquillizer Capillary fragility Plant Source Quisqualis indica Rauvolfia serpentina Rauvolfia serpentina Rhododendron molle Rorippa indica Lonchocarpus nicou Stephania sinica Citrus species

Plant Based Drugs and Medicines

Drug/Chemical Action/Clinical Use Plant Source

Sanguinarine Santonin Scillarin A Scopolamine Sennosides A, B Silymarin Sparteine Stevioside Strychnine

Dental plaque inhibitor Ascaricide Cardiotonic Sedative Laxative Antihepatotoxic Oxytocic Sweetner CNS stimulant

Salix alba
Sanguinaria canadensis Artemisia maritma Urginea maritima Datura species Cassia species Silybum marianum Cytisus scoparius Stevia rebaudiana Strychnos nux-vomica

Plant Based Drugs and Medicines

Drug/Chemical Taxol Teniposide a-

Action/Clinical Use Antitumor agent Antitumor agent

Plant Source Taxus brevifolia Podophyllum peltatum Cannabis sativa

Antiemetic, decrease Tetrahydrocannabinol( occular tension THC) Analgesic, sedative, traquillizer Antihypertensive Diuretic, vasodilator Diuretic, brochodilator Antifungal (topical)

Tetrahydropalmatine Tetrandrine Theobromine Theophylline Thymol

Corydalis ambigua Stephania tetrandra Theobroma cacao Theobroma cacao and others Thymus vulgaris

Plant Based Drugs and Medicines

Drug/Chemical Topotecan Trichosanthin Tubocurarine Valapotriates Vasicine Action/Clinical Use Abortifacient Skeletal muscle relaxant Sedative Cerebral stimulant Plant Source Trichosanthes kirilowii Chondodendron tomentosum Valeriana officinalis Vinca minor

Antitumor, anticancer agent Camptotheca acuminata

Vincristine Yohimbine Yuanhuacine Yuanhuadine

Antitumor, Antileukemic agent

Antitumor, Antileukemic agent Aphrodisiac Abortifacient Abortifacient

Catharanthus roseus
Catharanthus roseus Pausinystalia yohimbe Daphne genkwa Daphne genkwa