Posted by Probably, the most creative and productive pharmaceutical chemist of all time, Dr. Paul Adriaan Jan Janssen, was born 100 years ago, in 12 September 1926. „Dr. Paul”, as he was known and called by the entire scientific community, was an exceptionally gifted and passionate scientist, who revolutionized modern medicine and inspired a new generation of researchers. His life was dedicated to creating medicines that met the unmet needs of millions of patients. The company’s name Janssen Pharmaceutica N.V. came from Dr. Paul Janssen, who founded the firm in 1953.
During the second world war, Paul Janssen studied physics, biology, and chemistry at the Faculté Notre Dame de la Paix in Namur, in Belgium’s French speaking region of Wallonia. Those courses convinced him of the importance of chemistry to medicine and of the need to use chemical knowlegde to make scientific advances in therapies. In 1945 Paul Janssen began his medical studies in the Catholic University of Leuven. He interrupted this with an extended visit to the United States three years, later to gain a better understanding of world-wide research in chemistry and pharmacology. Already he was looking to develop original drugs and to focus on synthesizing molecules in order to find the relationship between their pharmacological structure and activity. After completing his studies in Leuven, the young medical student moved to Ghent, where he qualified. Paul Janssen then divided his time for several years between study trips abroad and part time teaching at the Institute of Pharmacology and Therapeutics at Ghent University.
There, Janssen came into close contact with the institute’s director, Professor Corneel Heymans, who had won the Nobel prize for medicine in 1938. (Heymans was awarded the prize for discovering how the body measures blood pressure and blood chemistry – such as oxygen and carbon dioxide levels – and transmits these signals to the brain to regulate respiration and heart rate.) Janssen and his research team at the Janssen Pharmaceutica in Beerse (Belgium), discovered more than 80 new medications across parasitology, infections, psychiatry, anesthesia and gastroenterology. Some of Dr. Janssen’s most notable and essential medicinal discoveries are as follows:
- Haloperidol (Haldol): A pioneering typical antipsychotic synthesized in 1958 that revolutionized the treatment of schizophrenia and allowed patients to be managed outside of institutions.
- Fentanyl: A powerful synthetic opioid analgesic created in 1959 that remains a cornerstone of modern anesthesia and pain management.
- Risperidone (Risperdal): An atypical antipsychotic that widened the neuroleptic spectrum for managing psychotic disorders.
- Loperamide (Imodium): A widely utilized oral anti-diarrheal medication.
- Diphenoxylate (Lomotil): An anti-diarrheal agent that was even packed for use during the NASA Apollo space program.
- Mebendazole (Vermox): A broad-spectrum anthelmintic medication highly effective against intestinal worm infestations.
- Ketoconazole (Nizoral): An early oral and topical azole antifungal agent that transformed mycology treatments. (also other antifungal „conazoles”)
- Etomidate: A short-acting intravenous hypnotic-anesthetic agent widely used for the induction of general anesthesia. (1)
Paul Janssen’s best known achievement is the development of an extremely potent pain killer drug, Fentanyl, which was first synthesized in 1960. Fentanyl citrate was first used as an intravenous anesthetic called Sublimaze®. (Fig.2)
Chemical structure of Fentanyl free base and Sublimaze® with 50 µg/mL Fentanyl citrate
Like other analgesics, it can produce insensitivity to pain without necessarily producing unconsciousness. In other forms, it is useful for treating breakthrough cancer pain or other types of moderate-to-severe chronic pain, including back pain and pain caused by sickle cell anemia. According to the Drug Enforcement Administration (DEA), prescriptions for all types of fentanyl citrate have increased from 0.5 million in 1994 to more than 5.7 million in 2003. (2)
Why is Paul Janssen’s life work of interest for cyclodextrin community?
The answer is hydroxypropyl-beta-cyclodextrin-enabled Itraconazol, the Sporanox® product. (Fig.3)
Fig.3. Sporanox® oral liquid formulation by Janssen Cilag (https://www.jnjlabels.com/ca/content/labelling/ /sporanox_caps_cpm.pdf)
SPORANOX® (itraconazole) Oral Solution contains 10 mg of itraconazole per mL, solubilized by 2-hydroxypropyl-β-cyclodextrin (400 mg/mL) as a non-covalent, molecular inclusion complex. SPORANOX® Oral Solution is clear and yellowish in color with a target pH of 2. Other ingredients are hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium saccharin, sorbitol, cherry flavor 1, cherry flavor 2 and caramel flavor.
The enhanced oral bioavailability of intraconazole from HPBCD-enabled oral formulation is demostrated by a number of papers. Concentrations of oral azoles in serum were compared in a single-dose pharmacologic study in mice. When hydroxypropyl-beta-cyclodextrin was used as a carrier and compared with a standard carrier, polyethylene glycol, drug concentrations determined by bioassay showed that the peak concentration and area under the concentration-time curve were greatly enhanced for itraconazole and saperconazole. (3)
References:
- Theodore H. Stanley, Talmage D. Egan, Hugo Van Aken A Tribute to Dr. Paul A. J. Janssen: Entrepreneur Extraordinaire, Innovative Scientist, and Significant Contributor to Anesthesiology Anesthesia & Analgesia 106(2):p 451-462, February 2008. | DOI: 10.1213/ane.0b013e3181605add
2. William G. Schulz, Fentanyl Chem. Eng. News Volume 83, Issue 25 June 20, 2005.
3. J S Hostetler, L H Hanson, D A Stevens Effect of cyclodextrin on the pharmacology of antifungal oral azoles Antimicrob Agents Chemother . 1992 Feb;36(2):477-80. doi: 10.1128/AAC.36.2.477.)
Featured image: Paul Janssen (source: wikipedia)