Life beyond Science Early Work 1986 1986 Early

Life beyond Science

Early Work 1986

1986 • • • Early Work Years at Sterling Drug Company Products Developed Pro-Drug Approach Hydroxychloroquine Formulations Danazol Pro-Drugs

Life Beyond Science

Bold Move to Business 1989 - 2002 • Electrician Loan + Proctosol is same as Anusol • State of the Art liquid Manufacturing + Sell when on Top of the game

Guerrilla Warfare Guerrilla Marketing Guerrilla Innovation

Guerrilla Tactics in Pharmaceutical Innovation and Testing Dr. V. Ravi Chandran R&D Practitioner Life Enhancing Technologies, LLC. Allen, TX USA

Normally to create an IPR of a large Pharma Company requires: + + Army of Good Creative Scientists R&D Funding equal to top 10 Pharma Companies combined A Decade or more years

But what we really have: One Scientist (myself) Enough resources for a lavish retirement in Caribbean Islands Getting old – not much time left

Questions in my mind: Do I develop one Molecule at a time? Do I develop all the Drugs at one shot? Platform Technology? What area do I apply this Technology?

Status in the early 2000 Efficacious Toxic I wanted to increase the efficacy and reduce the toxicity i. e. Increase the Therapeutic Index Drugs entering market Examples

Hail in the Guerrilla! Areas of human endeavor responsible for enhancing Quality of Life* 1. Computer Hardware and Software 2. Advances in Medicine * APh. A Conference in Seattle, Washington, USA Circa year 2000

Leading Causes of Death *JAMA Vol. 284, No. 4, July 26, 2000

Guerrilla Tactic – 1 : Narrow area of attack with maximum impact Among Heart Diseases, Heart Attack is the leading cause of death in both men and women* *World Health Report 2004. Changing History, WHO 2004 pp 120 -124 ISBN 92 -4 -156265 -K

Tribute to a Legend

CLASSICAL AGE OLD DRUG • Was Omar Sharif on Low Dose Aspirin? • What is Aspirin? • Chemically it is Acetyl Salicylic Acid

Guerrilla Tactic – 7 : Creativity turns Problems into Opportunities How to rapidly advance a NCE without an IND from Lab to Clinical Trials

Guerrilla Tactic – 8 : Simple Techniques are sometimes most useful What can be an effective, simple and reliable technique to measure effectiveness of anti-platelet drugs in humans

Beautiful & Handsome Arabs

Doc, Can you Sing & Dance?

Doc, Can you Act?

Outsource Hollywood?

Bollywood Dream Busted!

Guerrilla Tactic – 12 : Expand upon what worked earlier Expansion of OH Containing AA platform technology to improve Ibuprofen Synthesized 3 Amino Acid Esters of Racemic Ibuprofen L – Threonine L – Hydroxy Proline L - Serine

Numerous Surprises on Raviprofen® Surprising Racemic Separation L– Threonine Platform Technology Proven Works similar to Ibuprofen No Ibuprofen released Effective in Human Trials No Systemic Toxicity Not a Pro - Drug

Guerrilla Tactic – 13 : Open to surprises & turn them into advantages Yes! Can we separate racemic mixtures with L-Threonine? Ketoprofen & Ketorolac separated Embedded Platform Inside our Platform Technology

Painkiller Extraordinary L-Threonine Ester of S(-)Ketorolac Separates Racemic Mixtures Non Toxic No Addiction Potential Threonine Ester of S ( -) Ketorolac Highly Effective in Human Trials Narcotic Strength Pain reliever

L-Threonine – Nature’s Wonder Surprising Racemic Separation Platform Technology Proven Simple Separation Method Versatile Properties Effective for Non Racemic Drugs Resulting Isomer has high TI Not a Pro - Drug

Applications of Chiral Separation using L-Threonine Racemic Hydroxychloroquine S(-)R(+) Carvedilol

Problems of Hindered Alcohols – Cyclosporine-A Poor Solubility Poor Absorption Hindered OH Group Variable Pharmacokinetics Inconsistent Pharmacological Activity

Kera. Klear - Numerous Surprises Hindered Alcohol Problems Solved TI of 4. 5 Showed better Prophylaxis Versatile Application Amino Acid Ester of Cyclosporine Keraklear No ocular irritation Highly Soluble in Water Formulation stable over 18 months

Life Enhancing Technologies

Tribute to a Legend

Prodrugs(? ) of Propofol Mr. Jackson wanted a good night sleep US Patent No. 8, 173, 840

Propofol Dose Selection Drug Low Mid High Propofol 10 mg/kg 15 mg/kg 20 mg/kg Lysine Ester of Propofol 40 mg/kg 45 mg/kg 50 mg/kg Proline Ester of Propofol 25 mg/kg 30 mg/kg 35 mg/kg Glycine Ester of Propofol 30 mg/kg 35 mg/kg 40 mg/kg 10 Rats each, all doses, Propofol molar equivalent

Propofol Efficacy Studies Mr. Jackson wanted low toxicity Drug Low (min)/ No. died Mid (min)/ No. Died High min)/ No. Died Propofol 0 0 123 ± 34 0 178 ± 30 0 Lysine Ester of Propofol 0 0 0 5 546 ± 0 9 Proline Ester of Propofol 282 ± 162 1 421 ± 113 0 641 ± 138 2 Glycine Ester of Propofol 532 ± 217 0 300 ± 211 0 641 ± 138 1 Time of righting reflex (seconds)

Conclusions – Propofol Studies • Mr. Michael Jackson only wanted a good night sleep • Doses administered to him were toxic. • If he had used Glycine Ester of Propofol, he would have had a long night sleep, and would come out of the sleep unscathed. • Further studies in humans are warranted.

Summary Largest Drug Pipeline in the World 9000 molecules in 3 years Creative processes and Guerrilla tactics Numerous Patents covering 80% of the market Better Alternatives for 6 out of top 10 – $ 41 Bill in sales Better Alternatives for 68 out of top 200 – $ 120 Bill in sales

Be on the lookout for AAA – Once a day capsules, non-toxic, safe and effective cardio-protective agent S(-)Ketorolac- LThreonine Ester, a superior pain killer of narcotic strength, but with no addiction potential Kera. Klear optic drops for dry eyes …

You Can Achieve Anything

Isn’t it Truly Life Enhancing!

Thank You