Widened Scope of Drug Repurposing/Chiral Switches, Elements of Secondary Pharmaceuticals: The Quinine/Quinidine Case

Figures & data

Figure 1. Chemical structures of Cinchona alkaloids.

The IUPAC names of quinine and quinidine are (R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol and (S)-[(2R,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol, respectively. Note that the numbering of atoms in the IUPAC names differs from the conventional numbering of the atoms of quinine and quinidine.

Table 1. Definitions of terms.

Term	Definition	Ref.
Biopiracy	The appropriation and commercialization of indigenous technologies without adequate permission, acknowledgment or compensation	[27]
Chiral switch	A switch of a chiral drug to a stereoisomeric drug which comprises a switch in the status of chirality, e.g., racemate to single enantiomer, epimers to single enantiomer	[20–23]
Drug repurposing	A strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication	[14]
Enantiomer patent	A patent that claims a single enantiomer of a chiral drug that has been claimed previously in the corresponding basic (broader) patent as a racemate or as a mixture of diastereomers	[19]
Evergreening	Intellectual property-based evergreening is a business strategy to extend the duration of the effective protection derived or derivable from a portfolio of intellectual property rights in order to increase the appropriability of an innovation or a set of business-related innovations or technologies	[19]
Me-too drug	A drug within the same chemical class as another already on the market	[19]
Patent troll	A pejorative term for a company that uses a portfolio of patents not to produce products but solely to collect licensing fees or settlements on patent infringement from other companies	[27]
Obvious-to-try	A patentability criterion for establishing prima facie obviousness wherein it is examined whether a person skilled in the art would have possessed any reasonable expectation of success of obtaining a beneficial technical effect of the claimed invention	[19]
Pejorative	Expressing disapproval or criticism
Product hopping	The process by which a brand, as the patents on an older branded drug are expiring, uses its current dominant market position to switch doctors, pharmacists, and consumers to a newer version of the same (or similar) drug with later-expiring patents	[27]
Quasi-diastereomers	A pair of stereoisomers that are diastereomeric at a certain functionality
Quasi-enantiomers	A pair of diastereomers that are enantiomeric at a certain functionality	[32]
Quasi-racemate	An equimolar mixture of a pair of quasi-enantiomers	[32]
Quasi-scalemic mixture	A mixture of paired quasi-enantiomers that is neither a quasi-racemic mixture nor a mixture of pure quasi-enantiomers
Scalemic mixture (scalemate)	A mixture of paired enantiomers that is neither a racemic mixture (ee = 0) nor a mixture of pure enantiomers (ee = 1)
Secondary pharmaceutical patent	A patent that protects a range of aspects related to but other than the direct active pharmaceutical ingredient protected by the corresponding primary pharmaceutical patent	[19]
Teaching away	A reference may be said to teach away when a person skilled in the art, upon reading the reference, would be discouraged from following the path set out in the reference or would be led in a direction divergent from the path that was taken by the applicant	[27]
Unexpected results	A term used to assess the nonobviousness of a claimed invention; it needs to be shown to a nonobvious extent that the results were superior compared with the prior art, to a nonobvious extent	[19]

ee: Enantiomeric excess.

Figure 2. Chiral switch of the SCH 31925 mixture of diastereomers (epimers) to ramipril.

Table 2. US FDA New Drug Applications of quinidine and quinine medicines.

Quinidine (1S,3R,4S,8R,9S)	Quinine (1S,3R,4S,8S,9R)
Formula	Formula
NDA#006320	NDA#206
Brand name: Quinidine Hydrochloride	Brand name: not available
Active ingredient: quinidine hydrochloride (injection)	Active ingredient: quinine sulfate (tablets)
FDA approval date: 1947 (withdrawn 1973)	FDA approval date: 1938
Drug classification: not available	Drug classification: not available
Indication/use: cardiac arrhythmia	Indication/use: relief of minor aches and pains
NDA#007529	NDA#227
Brand name: Quinidine Gluconate	Brand name: not available
Active ingredient: quinidine gluconate (injection)	Active ingredient: quinine sulfate
FDA approval date: 12 July 1950 (withdrawn 2019)	FDA approval date: 1938
Drug classification: New Active Ingredient	Drug classification: not available
Indication/use: cardiac arrhythmia	Indication/use: not available
NDA#007529/S-010	NDA#805
Brand name: Quinidine Gluconate	Brand name: not available
Active ingredient: quinidine gluconate (injection)	Active ingredient: quinine bisulfate (vaginal jelly)
FDA approval date: 12 June 1991 (withdrawn 2019)	FDA approval date: 1938
Supplement category: Efficacy-New Indication	Drug classification: not available
Indication/use: cardiac arrhythmia and life-threatening Plasmodium falciparum malaria	Indication/use: feminine hygienic preparation
NDA#007529/S-013	NDA#4425
Brand name: Quinidine Gluconate	Brand name: not available
Active ingredient: quinidine gluconate (injection)	Active ingredient: quinine bisulfate
FDA approval date: 7 March 1994	FDA approval date: 1938
Supplement category: labeling	Drug classification: not available
Indication/use: life-threatening Plasmodium falciparum malaria, conversion of atrial fibrillation/flutter, ventricular arrhythmia	Indication/use: not available
NDA#012796	NDA#021799
Brand name: Quinidex^®	Brand name: Qualaquin^®
Active ingredient: quinidine sulfate (tablets)	Active ingredient: quinine sulfate (capsules)
FDA approval date: 21 February 1962 (withdrawn 2007)	FDA approval date: 12 August 2005
Drug classification: New Dosage Form	Drug classification: New Formulation
Indication/use: cardiac arrhythmia	Indication/use: uncomplicated Plasmodium falciparum malaria
NDA#012796/S-049
Brand name: Quinidex Extentabs^®
Active ingredient: quinidine sulfate (extended-release tablets)
FDA approval date: 16 August 2001 (withdrawn 2007)
Supplement category: labeling
Indication/use: cardiac arrhythmia
NDA#011642
Brand name: Cardioquin^®
Active ingredient: quinidine polygalacturonate (tablets)
FDA approval date: before 1960 (withdrawn 2000)
Drug classification: not available
Indication/use: cardiac arrhythmia
NDA#011642/S-012
Brand name: Cardioquin^®
Active ingredient: quinidine polygalacturonate (tablets)
FDA approval date: 16 June 1999
Supplement category: labeling
Indication/use: cardiac arrhythmia
NDA#021879
Brand name: Nuedexta^®
Active ingredients: dextromethorphan hydrobromide, quinidine sulfate (capsules)
FDA approval date: 29 October 2010
Drug classification: New Combination
Indication/use: pseudobulbar affect (PBA)

NDA: New drug application.

Table 3. Drug repurposing and chiral switch regulatory events regarding quinine and quinidine medicines.

	Quinidine/quinine, indication (period/year)	Quinidine/quinine repurposing (year)	Quinidine/quinine, repurposed indication
1.	Quinidine, malaria (historical)	Repurposing (before 1938)	Quinidine, cardiac arrhythmia
2.	Quinine, malaria (historical)	Repurposing (1938)	Quinine, minor indications
3.	Quinine, malaria (historical)	Repurposing/Chiral switch (1947–1950)	Quinidine, cardiac arrhythmia
4.	Quinidine, cardiac arrhythmia (1950)	Repurposing (1991)	Quinidine, severe malaria
5.	Quinidine, cardiac arrhythmia (1950)	Repurposing/Chiral switch (2005)	Quinine, uncomplicated malaria
6.	Quinidine, severe malaria (1991)	Repurposing/Chiral switch (2005)	Quinine, uncomplicated malaria
7.	Quinidine, cardiac arrhythmia (1950)	Repurposing (2010)	Dextromethorphan + Quinidine, pseudobulbar affect

Figure 3. Homochiral and heterochiral interactions: enantiomers versus racemate.

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