Thereof

Field of the Invention The present invention relates to the pharmaceutical use of hydroxychloroquine and chloroquine for the treatment of conditions including, but not limited to, malaria, lupus, rheumatoid arthritis and severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2).

Background Hydroxychloroquine and chloroquine are known pharmaceutical compounds that are currently used to treat acute cases of malaria as well as certain autoimmune disorders, such as Lupus and rheumatoid arthritis. Both hydroxychloroquine and chloroquine are taken in the form of oral pharmaceutical compositions. It is believed that hydroxychloroquine and chloroquine have a broad antiviral effect and there has been initial research showing that they may be efficacious in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Some initial anecdotal evidence reports success in treating patients with severe SARS-Cov-2, sometimes in combination with azithromycin. On this basis, there are active studies and significant international interest in the use of hydroxychloroquine and/or chloroquine for the treatment of SARS-Cov-2.

Both hydroxychloroquine and chloroquine are available in tablet form or in solutions for oral use. Both hydroxychloroquine and chloroquine are commonly available as the phosphate, sulfate, and hydrochloride salts. Most commonly chloroquine is dispensed in tablet form as a phosphate salt.

For treatment of malaria in adults, chloroquine is typically given as a daily dose of 250 mg base or 500 mg of the salt orally. It is anticipated that for treatment of SARS-Cov-2 a similar or identical dose would be given.

For treatment of malaria in adults, hydroxychloroquine is typically given as 200-400 mg daily dose of the base daily with a maximum dose of approximately 6.5mg/kg.

It is known that after ingestion hydroxychloroquine is metabolized by the cytochrome p450 pathway to N-desethylhydroxychloroquine and chloroquine is metabolized by the cytochrome p450 pathway to N-desethylchloroquine. It is these metabolites that are active within the body in the treatment of malaria, lupus, rheumatoid arthritis and severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2).

In particular, as part of the cytochrome p450 pathway, both hydrozychloroquine and chloroquine react with glutathione to open a ring structure and make them water soluble. Glutathione is found in the liver. Some individuals have deficiencies of glutathione and such individuals may not be able to metabolise either hydrozychloroquine or chloroquine, rendering any pharmaceutical composition containing hydrozychloroquine or chloroquine ineffective.

Glutathione

Glutathione occurs in most cells of the body in adequate amounts but some individuals have a deficiency. Such individuals are more likely to be unable to properly and completely metabolise hydroxychloroquine or chloroquine and, as a result, pharmaceutical compositions comprising hydroxychloroquine and/or chloroquine are unlikely to be completely effective in these individuals.

The reaction of glutathione with hdroxy chi oroqui ne results in the following compounds:

+

CH ₄

+

The methane is subsequently broken down by unknown mechanisms.

Chloroquine reacts with the glutathione in an equivalent manner.

As chloroquine and hydroxychloroquine are both potentially efficacious treatments for severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), there is a strong desire for improved pharmaceutical compositions comprising chloroquine and/or hydroxychloroquine. Summary

The present invention provides a pharmaceutical composition consisting of: a first pharmaceutically active portion consisting of hydroxychloroquine or a salt thereof and/or chloroquine or a salt thereof; a second pharmaceutically active portion consisting of one or more of glutathione, cysteine, acetylcysteine, alliin, bucillamine, carbocysteine, djenkolic acid, felinine, lanthionine, mecysteine hydrochloride, penicillamine cysteine disulphide, or any functional equivalent thereof; and optionally one or more excipients; wherein the molar ratio of the second pharmaceutically active portion to the first pharmaceutically active portion is at least 0.5:1.

It has been discovered that providing the pharmaceutical composition of the present invention can enhance the metabolization of the hydroxychloroquine or chloroquine by the cytochrome p450 enzyme pathway in the liver. This pathway involves liver enzymes reacting the hydroxychloroquine or chloroquine with the second pharmaceutically active portion and/or a user’s own glutathione store within the liver to open the hydroxychloroquine or chloroquine’ ring structures and make them water soluble. As set out above, hydroxychloroquine is metabolized by the cytochrome p450 pathway to N-desethylhydroxychloroquine and choloroquine is metabolized by the cytochrome p450 pathway to N-desethylchloroquine.

The pharmaceutical composition of the present invention may be either a tablet, caplet, solution or in any other form as is considered suitable.

In order for a molecule of hydroxychloroquine or choloroquine to be metabolized by the cytochrome p450 pathway at least one molecule of the second pharmaceutically active portion of the pharmaceutical composition of the present invention or a user’s own glutathione is required when the composition is ingested. That is, in order for there to be complete metabolization of the hydroxychloroquine and/or choloroquine there must be a molar ratio of glutathione, cysteine, acetylcysteine, alliin, bucillamine, carbocysteine, djenkolic acid, felinine, lanthionine, mecysteine hydrochloride, penicillamine cysteine disulphide, or any functional equivalent thereof to hydroxychloroquine and/or choloroquine in the liver of at least 1:1. Glutathione may come from the user’s own stores or the second pharmaceutically active component of the present invention may be utilized in place of the user’s own glutathione. In completely healthy patients the liver will already have a supply of glutathione such that it is not necessarily essential that the pharmaceutical composition of the present invention has a molar ratio of the second pharmaceutically active portion to the first pharmaceutically active portion of at least 1:1. Rather, molar ratios of 0.5:1, 0.6:1, 0.7:1, 0.8:1, or 0.9:1 may be sufficient depending on the specific patient and their glutathione stores, the amount of the first pharmaceutically active portion in the pharmaceutical composition, and the dosage frequency. However, in order to ensure that complete metabolization of hydroxychloroquine and/or choloroquine it may be generally preferable that the second pharmaceutically active portion is provided in a molar ratio of at least 1:1 with the first pharmaceutically active portion.

In embodiments of the invention the first pharmaceutically active portion consists of hydroxychloroquine or a salt thereof.

In embodiments of the invention the first pharmaceutically active portion consists of choloroquine or a salt thereof.

In embodiments of the invention the first pharmaceutically active portion consists of a mix of hydroxychloroquine or a salt thereof and a chloroquine or a salt thereof. In the such embodiments the ratio of hydroxychloroquine or a salt thereof to chloroquine or a salt thereof may be 0.1:0.9, 0.2:0.8, 0.3:0.7; 0.4:0.6, 0.5:0.5, 0.6:0.4, 0.7:0.3, 0.8:0.2, or 0.9:0.1.

The second pharmaceutically active compound may comprise glutathione, cysteine, acetylcysteine, alliin, bucillamine, carbocysteine, djenkolic acid, felinine, lanthionine, mecysteine hydrochloride, penicillamine cysteine disulphide, or any functional equivalent thereof. A compound functionally equivalent to the listed compounds is one that has an available S-H bond that can react with a double bond on the aromatic ring structures of hydroxychloroquine or choloroquine to open the ring structures to m ak e them water soluble.

Alternative embodiments of the invention provide a pharmaceutical composition consisting of: a first pharmaceutically active portion consisting of N-desethylhydroxychloroquine or a salt thereof and/or N-desethylchloroquine or a salt thereof; and optionally one or more excipients.

In the alternative embodiments of the invention hydroxychloroquine has been reacted to form N-desethylhydroxychloroquine or a salt thereof and/or chloroquine has been reacted to form N-desethylchloroquine or a salt thereof prior to formation of the pharmaceutical composition. This can be done in any manner apparent to the person skilled in the art and will include the reaction of hydroxychloroquine with glutathione or a functional equivalent and/or the reaction of chloroquine with glutathione or a functional equivalent.

In the alternative embodiments the first pharmaceutically active portion may consist of N- desethylchloroquine or a salt thereof. Alternatively, the first pharmaceutically active portion may consist of N-desethylhydroxychloroquine or a salt thereof. In further alternatives, the first pharmaceutically active portion may consist of a mix of N-desethylhydroxychloroquine or a salt thereof and N-desethylchloroquine or a salt thereof. If the first pharmaceutically active portion consists of a mix of N-desethylhydroxychloroquine or a salt thereof and N- desethylchloroquine or a salt thereof the ratio may be 0.1:0.9, 0.2:0.8, 0.3:0.7; 0.4:0.6, 0.5:0.5, 0.6:0.4, 0.7:0.3, 0.8:0.2, or 0.9:0.1.

The alternative embodiments of the invention are advantageous in that they provide the metabolites of hydroxychloroquine and/or chloroquine and therefore do not require a patient to have or utilize their own glutathione stores.

A pharmaceutical composition according to the present invention may comprise any suitable excipient. This includes, but is not limited to, sweeteners, flavouring agents, preservatives, and pH adjusters. Suitable sweeteners include, but are not limited to, sucralose, aspartame, acesulfame k and equivalents. It is considered that the skilled person will be able to determine suitable excipients for any specific composition according to the present invention.

A pharmaceutical composition according to the present invention may be used for the treatment of any indication for which hydroxychloroquine or choloroquine is indicated. This includes, but is not limited to, malaria, lupus, or rheumatoid arthritis. A pharmaceutical composition according to the present invention may be used for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2).