GB2594918A - A pharmaceutical composition comprising hydroxychloroquine, chloroquine, or metabolite thereof - Google Patents
A pharmaceutical composition comprising hydroxychloroquine, chloroquine, or metabolite thereof Download PDFInfo
- Publication number
- GB2594918A GB2594918A GB2004599.3A GB202004599A GB2594918A GB 2594918 A GB2594918 A GB 2594918A GB 202004599 A GB202004599 A GB 202004599A GB 2594918 A GB2594918 A GB 2594918A
- Authority
- GB
- United Kingdom
- Prior art keywords
- active portion
- pharmaceutically active
- pharmaceutical composition
- salt
- hydroxychloroquine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229960004171 hydroxychloroquine Drugs 0.000 title claims abstract description 35
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 title claims abstract description 32
- 229960003677 chloroquine Drugs 0.000 title claims abstract description 31
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
- 239000002207 metabolite Substances 0.000 title description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 108010024636 Glutathione Proteins 0.000 claims abstract description 21
- 229960003180 glutathione Drugs 0.000 claims abstract description 21
- 241001678559 COVID-19 virus Species 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 201000004792 malaria Diseases 0.000 claims abstract description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 8
- 206010025135 lupus erythematosus Diseases 0.000 claims abstract description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 6
- VUAFHZCUKUDDBC-SCSAIBSYSA-N (2s)-2-[(2-methyl-2-sulfanylpropanoyl)amino]-3-sulfanylpropanoic acid Chemical compound CC(C)(S)C(=O)N[C@H](CS)C(O)=O VUAFHZCUKUDDBC-SCSAIBSYSA-N 0.000 claims abstract description 5
- BOTADXJBFXFSLA-WHFBIAKZSA-N (2s)-2-amino-3-[[(2r)-2-amino-2-carboxyethyl]disulfanyl]-3-methylbutanoic acid Chemical compound OC(=O)[C@H](N)C(C)(C)SSC[C@H](N)C(O)=O BOTADXJBFXFSLA-WHFBIAKZSA-N 0.000 claims abstract description 5
- XUHLIQGRKRUKPH-GCXOYZPQSA-N Alliin Natural products N[C@H](C[S@@](=O)CC=C)C(O)=O XUHLIQGRKRUKPH-GCXOYZPQSA-N 0.000 claims abstract description 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 5
- JMQMNWIBUCGUDO-UHFFFAOYSA-N L-Djenkolic acid Natural products OC(=O)C(N)CSCSCC(N)C(O)=O JMQMNWIBUCGUDO-UHFFFAOYSA-N 0.000 claims abstract description 5
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims abstract description 5
- JMQMNWIBUCGUDO-WHFBIAKZSA-N L-djenkolic acid Chemical compound OC(=O)[C@@H](N)CSCSC[C@H](N)C(O)=O JMQMNWIBUCGUDO-WHFBIAKZSA-N 0.000 claims abstract description 5
- DWPCPZJAHOETAG-IMJSIDKUSA-N L-lanthionine Chemical compound OC(=O)[C@@H](N)CSC[C@H](N)C(O)=O DWPCPZJAHOETAG-IMJSIDKUSA-N 0.000 claims abstract description 5
- WHOHXJZQBJXAKL-DFWYDOINSA-N Mecysteine hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CS WHOHXJZQBJXAKL-DFWYDOINSA-N 0.000 claims abstract description 5
- XUHLIQGRKRUKPH-UHFFFAOYSA-N S-allyl-L-cysteine sulfoxide Natural products OC(=O)C(N)CS(=O)CC=C XUHLIQGRKRUKPH-UHFFFAOYSA-N 0.000 claims abstract description 5
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 claims abstract description 5
- 229960004308 acetylcysteine Drugs 0.000 claims abstract description 5
- XUHLIQGRKRUKPH-DYEAUMGKSA-N alliin Chemical compound OC(=O)[C@@H](N)C[S@@](=O)CC=C XUHLIQGRKRUKPH-DYEAUMGKSA-N 0.000 claims abstract description 5
- 235000015295 alliin Nutrition 0.000 claims abstract description 5
- 229960004272 bucillamine Drugs 0.000 claims abstract description 5
- 229960004399 carbocisteine Drugs 0.000 claims abstract description 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 235000018417 cysteine Nutrition 0.000 claims abstract description 5
- IFERABFGYYJODC-LURJTMIESA-N felinine Chemical compound OCCC(C)(C)SC[C@H](N)C(O)=O IFERABFGYYJODC-LURJTMIESA-N 0.000 claims abstract description 5
- 229960001155 mecysteine hydrochloride Drugs 0.000 claims abstract description 5
- DWPCPZJAHOETAG-UHFFFAOYSA-N meso-lanthionine Natural products OC(=O)C(N)CSCC(N)C(O)=O DWPCPZJAHOETAG-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960002433 cysteine Drugs 0.000 claims abstract description 4
- 230000037361 pathway Effects 0.000 description 8
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 7
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- WMYLYYNMCFINGV-CKCBUVOCSA-N (2s)-2-amino-5-[[(2r)-1-(carboxymethylamino)-1-oxo-3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O.OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O WMYLYYNMCFINGV-CKCBUVOCSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
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 is provided. The second active portion preferably consists of glutathione. The pharmaceutical composition for use in the treatment of malaria, lupus, rheumatoid arthritis, or severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is provided. A pharmaceutical composition consisting of a first pharmaceutically active portion consisting of N-desethylhydroxychloroquine and/or N-desethylchloroquine or a salt thereof; and optionally one or more excipients is disclosed.
Description
A Pharmaceutical Composition Comprising Hydroxychloroquine, Chloroquine, or Metabolite 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. a
Chloroqu ne
COH
HN-Cl
Hydroxychloroquine 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.
SH
HO OH NH2
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 hdroxychloroquine results in the following compounds: CH4 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, 15 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 tabletcaplet, 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 I: I. 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 make them water soluble.
Alternative embodiments of the invention provide a pharmaceutical composition consisting 20 of: a first pharmaceutically active portion consisting of N-desethylhydroxy-chloroquine 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-desethylchloroqume 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, O. 6: 0.4, O. 7:0. 3, O. 8: 0.2, or O. 9: O. 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).
Claims (9)
- Claims 1. 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.
- 2 A pharmaceutical composition according to claim 1, wherein the molar ratio of the second pharmaceutically active portion to the first pharmaceutically active portion is at least 0.8:1.
- 3. A pharmaceutical composition according to claim 1, wherein the molar ratio of the second pharmaceutically active portion to the first pharmaceutically active portion is at least 1: I.
- 4. A pharmaceutical composition according to any preceding claim, wherein the first active portion consists of hydroxychloroquine or a salt thereof.
- 5. A pharmaceutical composition according to any of claims 1 to 3, wherein the first active portion consists of chloroquine or a salt thereof
- 6. A pharmaceutical composition according to claim 1, wherein the second pharmaceutically active portion consists of glutathione.
- 7 A pharmaceutical composition consisting of: a first pharmaceutically active portion consisting of N-desethylhydroxychloroquine and/or N-desethylchloroquine or a salt thereof; and optionally one or more excipients.
- 8. A pharmaceutical composition according to any preceding claim for use in the treatment of malaria, lupus, or rheumatoid arthritis.
- 9. A pharmaceutical composition according to any preceding claim for use in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2).S
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2004599.3A GB2594918A (en) | 2020-03-30 | 2020-03-30 | A pharmaceutical composition comprising hydroxychloroquine, chloroquine, or metabolite thereof |
| PCT/EP2021/057836 WO2021198041A1 (en) | 2020-03-30 | 2021-03-25 | A pharmaceutical composition comprising hydroxychloroquine, chloroquine, or metabolite thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2004599.3A GB2594918A (en) | 2020-03-30 | 2020-03-30 | A pharmaceutical composition comprising hydroxychloroquine, chloroquine, or metabolite thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB202004599D0 GB202004599D0 (en) | 2020-05-13 |
| GB2594918A true GB2594918A (en) | 2021-11-17 |
Family
ID=70553569
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB2004599.3A Withdrawn GB2594918A (en) | 2020-03-30 | 2020-03-30 | A pharmaceutical composition comprising hydroxychloroquine, chloroquine, or metabolite thereof |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2594918A (en) |
| WO (1) | WO2021198041A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190070166A1 (en) * | 2017-09-02 | 2019-03-07 | Richard Postrel | Optimized Method for Treating and Curing Arthritis, Diabetes, Multiple Sclerosis and Other Autoimmune Disease |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140275257A1 (en) * | 2013-03-14 | 2014-09-18 | Foundation for the State University of New York | N-acetyl cysteine compositions in the treatment of systemic lupus erythematosus |
| US9616057B2 (en) * | 2013-03-15 | 2017-04-11 | The Board Of Trustees Of The Leland Stanford Junior University | Desethylhydroxychloroquine for the treatment of diseases associated with inflammation |
| CN112386595A (en) * | 2020-03-09 | 2021-02-23 | 徐静 | Pharmaceutical composition for treating viral infection of respiratory system |
-
2020
- 2020-03-30 GB GB2004599.3A patent/GB2594918A/en not_active Withdrawn
-
2021
- 2021-03-25 WO PCT/EP2021/057836 patent/WO2021198041A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190070166A1 (en) * | 2017-09-02 | 2019-03-07 | Richard Postrel | Optimized Method for Treating and Curing Arthritis, Diabetes, Multiple Sclerosis and Other Autoimmune Disease |
Non-Patent Citations (5)
| Title |
|---|
| Autoimmunity Reviews, vol. 8, no. 8 2009, pages 697-701 * |
| Latin American Journal of Pharmacy, vol. 34, no. 6, 2015, pages 1269-1272 * |
| Marisa Zeppieri, 18 July 2019, "4 Benefits of Glutathione for lupus", lupuschick.com, [online], Available from https://lupuschick.com/4-benefits-of-glutathione-for-lupus/ [Accessed 3 September 2021] * |
| Seminars in arthritis and rheumatism, vol. 23, no. 2, pages 82-91 * |
| Terry Lemerond, 23 February 2015, "The master antioxidant: Glutathione has far-reaching benefits", chiroeco.com, [online], Available from https://www.chiroeco.com/master-antioxidant-glutathione/ [Accessed 3 September 2021] * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021198041A1 (en) | 2021-10-07 |
| GB202004599D0 (en) | 2020-05-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5846822B2 (en) | Nutritional or therapeutic composition | |
| US5866617A (en) | Formulations and methods of use 2,2'-dithio-bis-esthane sulfonate | |
| US20060189584A1 (en) | Pharmaceutical combinations | |
| WO1994008628A1 (en) | Prevention of acetaminophen overdose toxicity with organosulfur compounds | |
| JPH11509547A (en) | Pharmaceutical composition of L-dopa ethyl ester | |
| PT867179E (en) | COMPOSITION OF L-DOPA ESTERS | |
| Miihlbauer et al. | Magnesium-L-aspartate-HCI and magnesium-oxide: bioavailability in healthy volunteers | |
| AU675412B2 (en) | Method of treating HIV infection | |
| JPH06501000A (en) | How to increase glutathione levels using glutamine | |
| US5554655A (en) | Method of treating HIV infection | |
| US5100898A (en) | Antitussive liquid compositions containing dyclonine | |
| GB2594918A (en) | A pharmaceutical composition comprising hydroxychloroquine, chloroquine, or metabolite thereof | |
| JPH01246221A (en) | Phenol-containing antitussive agent | |
| AU2002363874B2 (en) | Use of desoxypeganine for treating clinical depression | |
| CA1273875A (en) | Antiinflammatory compositions and methods | |
| JPH04312527A (en) | Method of treating hepatic inssuficiency and liver disease | |
| US3822344A (en) | Pharmaceutical compositions providing potassium chloride in aqueous solution | |
| US6077838A (en) | Method of treating hangover | |
| US4558050A (en) | Treatment of metabolic disorders with dichloroacetate-thiamine preparations | |
| AU651824B2 (en) | Pharmaceutical composition | |
| JPH0952832A (en) | Medicinal composition | |
| US20050054688A1 (en) | Selective serotonin reuptake inhibitors in the treatment of disease | |
| JP2545321B2 (en) | Smooth muscle contraction inhibitor | |
| EP0935964A1 (en) | Pharmaceutical compositions containing NSAIDs and piperine | |
| JP2905231B2 (en) | Alcohol absorption inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |