WO2022123323A1 - A pharmaceutical composition of artesunate and mefloquine and method thereof - Google Patents

A pharmaceutical composition of artesunate and mefloquine and method thereof Download PDF

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Publication number
WO2022123323A1
WO2022123323A1 PCT/IB2021/050439 IB2021050439W WO2022123323A1 WO 2022123323 A1 WO2022123323 A1 WO 2022123323A1 IB 2021050439 W IB2021050439 W IB 2021050439W WO 2022123323 A1 WO2022123323 A1 WO 2022123323A1
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Prior art keywords
pharmaceutical composition
mefloquine
artesunate
amount
present
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PCT/IB2021/050439
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French (fr)
Inventor
Chander Mohan Negi
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Menschlich Healthcare (Opc) Private Limited
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Publication of WO2022123323A1 publication Critical patent/WO2022123323A1/en

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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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

Definitions

  • Embodiments of a present disclosure relate to a technical field of pharmaceutical composition. More particularly, the present disclosure relates to pharmaceutical composition that includes a synergistic combination of Artesunate and Mefloquine.
  • coronavirus disease is an infectious disease caused by a newly discovered coronavirus.
  • the disease emerged first in December 2019 in Wuhan, Hubei, China.
  • This deadly disease rapidly spread to almost 188 countries around the world, with a mortality rate of approximately 5%.
  • the outbreak was declared a Public health Emergency of International Concern by the World Health Organization (WHO) in January 2020 and was recognized as a pandemic in March 2020.
  • WHO World Health Organization
  • SARS-CoV coronavirus
  • SARS-CoV is an enveloped, positive-strand RNA virus. Its large RNA genome is approximately 30000 nucleotides in length and encodes a nonstructural replicase complex and structural proteins, including spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins.
  • Spike protein is the envelope protein responsible for invasion of host cells.
  • COVID positive individual may remain asymptomatic or show symptoms that may be common, mild in nature or severe. Most common symptoms of COVID 19 positive range from fever, dry cough, tiredness, etc., ranging to less common symptoms such as body aches and pains, sore throat, diarrhea, conjunctivitis, severe headache and loss of taste or smell and appearance of rash on skin, or discoloration of fingers or toes.
  • COVID 19 is fatal if the affected individual develops serious symptoms such as difficulty in breathing or shortness of breath, chest pain or pressure and loss of speech or movement. In case COVID 19 is detected early on and the affected person takes the due care it has been seen that mild and less serious symptoms can be controlled and overcome. As most of COVID 19 early symptoms are curable, an effective medicine can be formulated with use of existing pharmaceutical salts.
  • the manufacturing of the new drug possesses various challenges. Whenever the drug starts new clinical trials, there are lots of problems that needs to be overcome, such as drug safety, patient selection, trial dose and other issues. Even after the drug has been approved by the regulatory authorities and sales on the market, they still may possibly face the situation of the poor drug response in patients.
  • the current invention is comprised of such novel composition which has been effectively selected and is proven to be effective in treatment of COVID 19(SARS-CoV2).
  • compositions comprising artesunate and mefloquine there remains a substantial need in the art for new and improved pharmaceutical composition of artesunate and mefloquine. Even though range of prior arts discloses use of pharmaceutical composition comprising Artesunate with Mefloquine or other APIs.US20050148628Al and W02003075927A1 discloses a pharmaceutical compositions of Artesunate and Mefloquine, this pharmaceutical compositions are particularly disclosed as useful for treatment of malaria.
  • composition comprising a simple, easy to manufacture and therapeutically effective dosage regime.
  • a pharmaceutical composition for treating Covid- 19 virus comprising a therapeutically effective amount of an artesunate or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises the artesunate in the ratio of 0.25% to 66% w/v. In accordance with an embodiment of the present invention, the pharmaceutical composition comprises the mefloquine in the ratio of 0.25% to 90% w/v.
  • the pharmaceutical composition comprises at least one of pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises at least one of pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a granule, tablet, capsule, liquid, or mixture pellets.
  • the pharmaceutical composition can be administered as oral, parental, topical or any other mode of administration.
  • the amount of artesunate is 20-1000mg then the amount of mefloquine is 50-1500mg.
  • the amount of artesunate is 20-550mg, preferably 100-200mg then the amount of mefloquine is 100-750mg, preferably 100-500mg.
  • the amount of artesunate is lOOmg then the amount of mefloquine is 200mg.
  • the amount of artesunate is 200mg then the amount of mefloquine is 200mg.
  • the pharmaceutical composition is also used in the treatment of Hepatitis B, Hepatitis C and Chikungunya virus.
  • the combined preparation comprises of one or more dosage units of an artesunate or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof.
  • the COVID-19(SARS-CoV-2) is an ongoing pandemic of Corona virus disease 2019(COVID-19). It is an infectious disease caused by newly discovered Severe acute respiratory syndrome Corona virus 2 (SARS-CoV-2).
  • the disease (SARS- CoV-2) can spread from person to person through small droplets from the nose or mouth land on objects and surfaces around the person which are spread when a person with COVID- 19 coughs or exhales.
  • the SARS presents as atypical pneumonia that often leads to acute respiratory distress syndrome and respiratory failure, the main cause of death. This unusual infectious disease has become a major threat to public health and social stability since its outbreak.
  • Embodiments of the present invention relates to a pharmaceutical composition for treating Covid- 19 virus comprising a therapeutically effective amount of an artesunate or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition comprises the artesunate in the ratio of 0.25% to 66% w/v.
  • the pharmaceutical composition comprises the mefloquine in the ratio of 0.25% to 90% w/v.
  • Artesunate is Artemisinin derivative which is a medication used to treat malaria and Mefloquine is a quinolinemethanol derivative with antimalarial, anti-inflammatory, and potential chemo-sensitization and radio- sensitization activities. Mefloquine is used to both prevent and treat certain forms of malaria.
  • Artesunate combines synergistically with Mefloquine and this combination exhibited promising In- Vitro antiviral activity against SARS-CoV2. Therefore, this promising In-Vitro results renders the Artesunate and Mefloquine combination a good candidate for its use in drug combination therapy for SARS-CoV2 infections.
  • the combination of therapeutic effective amount of Artesunate and Mefloquine are shown to be rapidly effective and produce faster resolution of SARS-CoV2 and fever than all other identified compounds.
  • the pharmaceutical composition comprising Artesunate along with Mefloquine were found to limit virus entry, reduces virus particles, inhibit both viral release and cell-to-cell transmission, and possess broad anti-viral activities which makes the purposing of existing drugs a timely and attractive alternative.
  • the pharmaceutical composition comprises at least one of pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises at least one of pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is selected from one or more of the group consisting of mannitol, sorbitol, a sorbic acid or potassium salt, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin A, vitamin C, vitamin E, vitamin D, azone, disodium ethylenediaminetetraacetate, calcium sodium ethylenediaminetetraacetate, monovalent alkali metal carbonate, acetate, phosphate or an aqueous solution thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dex
  • the pharmaceutical composition is a granule, tablet, capsule, oral, liquid, or mixture pellets.
  • the pharmaceutical composition can be administered as oral, parental, topical or any other mode of administration.
  • the combined preparation comprises of one or more dosage units of an artesunate or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable excipients are selected from the group comprising diluents/fillers, binders, disintegrants, glidants, lubricants, solubilizers/surfactants/wetting agents, plasticizers, solvents and the like.
  • the pharmaceutical compositions of the present invention can be in the form of modified release dosage form which include, but not limited to, controlled release, sustained release, extended release, prolonged release dosage form.
  • modified release dosage form which include, but not limited to, controlled release, sustained release, extended release, prolonged release dosage form.
  • rate controlling agents/techniques known in the art may be used to control the release of the drug from the dosage form.
  • the pharmaceutical composition may be in the form of tablets, capsules, tablets filled in capsule, minitablets filled in capsule, sachets containing powder or granules, pellets, and the like.
  • the pharmaceutical composition is meant for once daily or twice daily administration.
  • the teachings of the present invention relates to the combination of Artesunate and Mefloquine administrations that improves the dosage regimen and combinational therapy that is not only effective and safe but also simple in administration resulting in a maximum of patients' compliance.
  • Current therapy in the prior art has been found to be vulnerable, if the strategy requires several drugs to be taken at different days and times.
  • the rapid alleviation of symptoms due to the effect of several dosage often leads to abrupt end of the therapy as the patient feels well. This leads to high risk of recurrence of the disease and the development of severity due to an insufficient treatment.
  • Compliance of the patient is, therefore, a crucial consideration and a key determinant in the successful treatment of COVID regarding both efficacy of the therapy and prevention of recurrence. Long duration regimens, complex dosing schemes, poor understanding of the patient of how or why to adhere to the recommended regimen as well as rapid perception of wellness induce the patient to discontinue the therapy prematurely.
  • a combination of Artesunate and Mefloquine has been found that it provides a simple fixed-dose treatment administered one to two times a day for 3-10 days. This combination is unexpectedly well tolerated with a low rate of side-effects, and equally high curerates than in comparable treatments. Due to the simple dosing regimen the patients' compliance is excellent.
  • fixed-dose means daily dosage of both antiviral that are same every day for a given treatment course, wherein the amount of the effective dose can be individually determined by the medical practitioner.
  • a method for the treatment of SARS-CoV2 in a 3-10 day course is also provided administering a therapeutically effective amount of the combination of Artesunate and Mefloquine is provided, wherein the dosage of Artesunate and Mefloquine for each day remains the same.
  • the amount of the combination of Artesunate and Mefloquine required to be effective as an antiviral will, of course, vary and is ultimately at the discretion of the medical practitioner.
  • the factors to be considered include the nature and severity of the SARS-CoV2 infection to be treated, route of administration, high or low transmission area, the immune status of the patient as well as age and weight of the patient.
  • the present invention provides a pharmaceutical composition for treatment of SARS-CoV2 with existing pharmaceutical APIs and salts in novel composition
  • the respective raw materials, pharmaceutically acceptable carrier and an extract can be prepared as granules, tablets, capsules, oral liquid, or mixture pellets.
  • the pharmaceutical composition can be a tablet, carrier as lactose or corn starch, magnesium stearate lubricants are added when required, mixed well, and then tableted.
  • the powder when the present invention is made in capsules, the powder is filled in required doses in the capsule shells to form capsules.
  • the amount of artesunate is 20-1000mg then the amount of mefloquine is 50-1500mg.
  • the amount of artesunate is 20-550mg, preferably 100-200mg then the amount of mefloquine is 100-750mg, preferably 100-500mg.
  • the amount of artesunate is lOOmg then the amount of mefloquine is 200mg.
  • the amount of artesunate is 200mg then the amount of mefloquine is 200mg.
  • the dosage of the pharmaceutical composition in the present invention can carry out suitable variation according to the dosage form difference of administration object, route of administration or medicine, but take, guarantees that this pharmaceutical composition can reach effective blood drug level as prerequisite in mammalian body.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A pharmaceutical composition for treating Covid-19 virus comprising a therapeutically effective amount of an artesunate or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof is disclosed. The pharmaceutical composition comprises the artesunate in the ratio of 0.25% to 66% w/v and mefloquine in the ratio of 0.25% to 90% w/v. The composition is found to be effective for the treatment of COVID-19 (SARS-CoV2). The pharmaceutical composition of Artesunate and Mefloquine has been found to be effective and is unexpectedly well tolerated with a low rate of side-effects, and equally high cure-rates than in comparable treatments. The present invention also discloses a method to preparing the pharmaceutical composition comprising of Artesunate and Mefloquine.

Description

A PHARMACEUTICAL COMPOSITION OF ARTESUNATE AND MEFLOQUINE AND METHOD THEREOF
This International Application claims priority from a Patent application filed in India having Patent Application No. 202021053551, filed on December 09, 2020, and titled “A PHARMACEUTICAL COMPOSITION OF ARTESUNATE AND MEFLOQUINE AND METHOD THEREOF”.
FIELD OF INVENTION
Embodiments of a present disclosure relate to a technical field of pharmaceutical composition. More particularly, the present disclosure relates to pharmaceutical composition that includes a synergistic combination of Artesunate and Mefloquine.
BACKGROUND
It is known that coronavirus disease (COVID- 19) is an infectious disease caused by a newly discovered coronavirus. The disease emerged first in December 2019 in Wuhan, Hubei, China. This deadly disease rapidly spread to almost 188 countries around the world, with a mortality rate of approximately 5%. The outbreak was declared a Public health Emergency of International Concern by the World Health Organization (WHO) in January 2020 and was recognized as a pandemic in March 2020. As of 6 October 2020, more than 35.4 million cases have been reported in 188 Countries and territories worldwide, although the true number of cases is likely to be much higher. As per the record more than 1.04 million deaths attributed to COVID-19 as on date.
A novel coronavirus, (SARS-CoV), was identified as the etiological agent of SARS. SARS-CoV is an enveloped, positive-strand RNA virus. Its large RNA genome is approximately 30000 nucleotides in length and encodes a nonstructural replicase complex and structural proteins, including spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins. Spike protein is the envelope protein responsible for invasion of host cells.
It has been found that COVID positive individual may remain asymptomatic or show symptoms that may be common, mild in nature or severe. Most common symptoms of COVID 19 positive range from fever, dry cough, tiredness, etc., ranging to less common symptoms such as body aches and pains, sore throat, diarrhea, conjunctivitis, severe headache and loss of taste or smell and appearance of rash on skin, or discoloration of fingers or toes.
COVID 19 is fatal if the affected individual develops serious symptoms such as difficulty in breathing or shortness of breath, chest pain or pressure and loss of speech or movement. In case COVID 19 is detected early on and the affected person takes the due care it has been seen that mild and less serious symptoms can be controlled and overcome. As most of COVID 19 early symptoms are curable, an effective medicine can be formulated with use of existing pharmaceutical salts.
Otherwise, the manufacturing of the new drug possesses various challenges. Whenever the drug starts new clinical trials, there are lots of problems that needs to be overcome, such as drug safety, patient selection, trial dose and other issues. Even after the drug has been approved by the regulatory authorities and sales on the market, they still may possibly face the situation of the poor drug response in patients.
The current invention is comprised of such novel composition which has been effectively selected and is proven to be effective in treatment of COVID 19(SARS-CoV2).
Although several approaches have been reported in the art with respect to compositions comprising artesunate and mefloquine, there remains a substantial need in the art for new and improved pharmaceutical composition of artesunate and mefloquine. Even though range of prior arts discloses use of pharmaceutical composition comprising Artesunate with Mefloquine or other APIs.US20050148628Al and W02003075927A1 discloses a pharmaceutical compositions of Artesunate and Mefloquine, this pharmaceutical compositions are particularly disclosed as useful for treatment of malaria.
Hence, there is a need for a pharmaceutical composition and process for preparation of the same to satisfy the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.
OBJECTIVE OF THE INVENTION
In accordance with an embodiment of the present invention, it is the object of the present invention to provide an effective pharmaceutical composition for treatment of COVID-19 (SARS-CoV-2).
In accordance with an embodiment of the present invention, it is another object of the present invention to provide a method of production of a pharmaceutical composition comprising Artesunate and Mefloquine.
In accordance with an embodiment of the present invention, it is further object of the present invention to provide a composition comprising a simple, easy to manufacture and therapeutically effective dosage regime.
SUMMARY OF THE INVENTION
In accordance with an embodiment of the present invention, a pharmaceutical composition for treating Covid- 19 virus comprising a therapeutically effective amount of an artesunate or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof.
In accordance with an embodiment of the present invention, the pharmaceutical composition comprises the artesunate in the ratio of 0.25% to 66% w/v. In accordance with an embodiment of the present invention, the pharmaceutical composition comprises the mefloquine in the ratio of 0.25% to 90% w/v.
In accordance with an embodiment of the present invention, the pharmaceutical composition comprises at least one of pharmaceutically acceptable excipient.
In accordance with an embodiment of the present invention, the pharmaceutical composition comprises at least one of pharmaceutically acceptable carrier.
In accordance with an embodiment of the present invention, the pharmaceutical composition is a granule, tablet, capsule, liquid, or mixture pellets.
In accordance with an embodiment of the present invention, the pharmaceutical composition can be administered as oral, parental, topical or any other mode of administration.
In accordance with an embodiment of the present invention, wherein when the amount of artesunate is 20-1000mg then the amount of mefloquine is 50-1500mg.
In accordance with an embodiment of the present invention, wherein when the amount of artesunate is 20-550mg, preferably 100-200mg then the amount of mefloquine is 100-750mg, preferably 100-500mg.
In accordance with an embodiment of the present invention, wherein the amount of artesunate is lOOmg then the amount of mefloquine is 200mg.
In accordance with an embodiment of the present invention, wherein the amount of artesunate is 200mg then the amount of mefloquine is 200mg.
In accordance with an embodiment of the present invention, wherein the pharmaceutical composition is also used in the treatment of Hepatitis B, Hepatitis C and Chikungunya virus.
In accordance with an embodiment of the present invention, the combined preparation comprises of one or more dosage units of an artesunate or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof.
To further clarify the advantages and features of the present invention, a more particular description of the invention will follow by reference to specific embodiments thereof, which are illustrated in the appended figures. It is to be appreciated that these figures depict only typical embodiments of the invention and are therefore not to be considered limiting in scope. The invention will be described and explained with additional specificity and detail with the appended figures.
DETAILED DESCRIPTION
For the purpose of promoting an understanding of the principles of the disclosure, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe them. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended. Such alterations and further modifications in the illustrated system, and such further applications of the principles of the disclosure as would normally occur to those skilled in the art are to be construed as being within the scope of the present disclosure.
The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such a process or method. Similarly, one or more components, compounds, and ingredients preceded by "comprises... a" does not, without more constraints, preclude the existence of other components or compounds or ingredients or additional components. Appearances of the phrase "in an embodiment", "in another embodiment" and similar language throughout this specification may, but not necessarily do, all refer to the same embodiment. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The system, methods, and examples provided herein are only illustrative and not intended to be limiting.
In the following specification and the claims, reference will be made to a number of terms, which shall be defined to have the following meanings. The singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.
The COVID-19(SARS-CoV-2) is an ongoing pandemic of Corona virus disease 2019(COVID-19). It is an infectious disease caused by newly discovered Severe acute respiratory syndrome Corona virus 2 (SARS-CoV-2). The disease (SARS- CoV-2) can spread from person to person through small droplets from the nose or mouth land on objects and surfaces around the person which are spread when a person with COVID- 19 coughs or exhales. The SARS presents as atypical pneumonia that often leads to acute respiratory distress syndrome and respiratory failure, the main cause of death. This unusual infectious disease has become a major threat to public health and social stability since its outbreak.
Despite massive international attempts to stop this COVID & SARS-CoV2, it remains a serious pandemic disease around the world. One of the major factors contributing to the continued presence of SARS-CoV2 is that there is no promising therapy available for the disease and the traditional drug development processes are slow and not very effective against emerging public health threats such as the current SARS-CoV-2 coronavirus outbreak.
Embodiments of the present invention relates to a pharmaceutical composition for treating Covid- 19 virus comprising a therapeutically effective amount of an artesunate or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof. In accordance with an embodiment of the present invention, the pharmaceutical composition comprises the artesunate in the ratio of 0.25% to 66% w/v.
In accordance with an embodiment of the present invention, the pharmaceutical composition comprises the mefloquine in the ratio of 0.25% to 90% w/v.
Chemically, Artesunate is Artemisinin derivative which is a medication used to treat malaria and Mefloquine is a quinolinemethanol derivative with antimalarial, anti-inflammatory, and potential chemo-sensitization and radio- sensitization activities. Mefloquine is used to both prevent and treat certain forms of malaria.
When Artesunate and Mefloquine are used alone not in combination, despite, their excellent intrinsic antimalarial activity, they have not shown the any effective results for the treatment against SARS-CoV2 infection.
According to an embodiment of the present invention, Artesunate combines synergistically with Mefloquine and this combination exhibited promising In- Vitro antiviral activity against SARS-CoV2. Therefore, this promising In-Vitro results renders the Artesunate and Mefloquine combination a good candidate for its use in drug combination therapy for SARS-CoV2 infections.
According to an embodiment of the present invention, the combination of therapeutic effective amount of Artesunate and Mefloquine are shown to be rapidly effective and produce faster resolution of SARS-CoV2 and fever than all other identified compounds.
According to an embodiment of the present invention, the pharmaceutical composition comprising Artesunate along with Mefloquine were found to limit virus entry, reduces virus particles, inhibit both viral release and cell-to-cell transmission, and possess broad anti-viral activities which makes the purposing of existing drugs a timely and attractive alternative.
According to an embodiment of the present invention, the pharmaceutical composition comprises at least one of pharmaceutically acceptable excipient. According to an embodiment of the present invention, the pharmaceutical composition comprises at least one of pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is selected from one or more of the group consisting of mannitol, sorbitol, a sorbic acid or potassium salt, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin A, vitamin C, vitamin E, vitamin D, azone, disodium ethylenediaminetetraacetate, calcium sodium ethylenediaminetetraacetate, monovalent alkali metal carbonate, acetate, phosphate or an aqueous solution thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, a silicon derivative, cellulose and a derivative thereof, alginate, gelatine, polyvinylpyrrolidone, glycerol, propylene glycol, ethanol , Tween 60-80, Span- 80, beeswax, lanolin, liquid paraffin, cetyl alcohol, a gallic acid ester, agar, triethanolamine, a basic amino acid, urea, allantoin, calcium carbonate, calcium bicarbonate, a surfactant, polyethylene glycol, cyclodextrin, 0-cyclodextrin, a phospholipid material, kaolin, talc, calcium stearate, magnesium, stearate, microcrystalline, poloxamer 407, poloxamer 188, phenethyl alcohol, methyl paraben, ethylparaben, benzalkonium bromide, sorbic acid, propylene glycol, polyethylene glycol 400, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, glycerine, mannitol, sorbitol, glucose, sodium chloride, and potassium chloride.
According to an embodiment of the present invention, the pharmaceutical composition is a granule, tablet, capsule, oral, liquid, or mixture pellets.
According to an embodiment of the present invention, the pharmaceutical composition can be administered as oral, parental, topical or any other mode of administration.
According to an embodiment of the present invention, the combined preparation comprises of one or more dosage units of an artesunate or its pharmaceutically acceptable salts thereof and a mefloquine or its pharmaceutically acceptable salts thereof.
According to an embodiment of the present invention, the pharmaceutically acceptable excipients are selected from the group comprising diluents/fillers, binders, disintegrants, glidants, lubricants, solubilizers/surfactants/wetting agents, plasticizers, solvents and the like.
According to one embodiment of the present invention, the pharmaceutical compositions of the present invention can be in the form of modified release dosage form which include, but not limited to, controlled release, sustained release, extended release, prolonged release dosage form. Various rate controlling agents/techniques known in the art may be used to control the release of the drug from the dosage form.
According to an embodiment of the present invention, the pharmaceutical composition may be in the form of tablets, capsules, tablets filled in capsule, minitablets filled in capsule, sachets containing powder or granules, pellets, and the like. The pharmaceutical composition is meant for once daily or twice daily administration.
EXAMPLE OF PREPARATION OF ARTESUNATE AND MEFLOQUINE FORMULATIONS
The preparation of film coated tablets having some of the ingredients as listed below which can either include or exclude when prepared using conventional techniques:
Figure imgf000010_0001
Figure imgf000011_0001
Thus, the teachings of the present invention relates to the combination of Artesunate and Mefloquine administrations that improves the dosage regimen and combinational therapy that is not only effective and safe but also simple in administration resulting in a maximum of patients' compliance. Current therapy in the prior art has been found to be vulnerable, if the strategy requires several drugs to be taken at different days and times. In addition, the rapid alleviation of symptoms due to the effect of several dosage often leads to abrupt end of the therapy as the patient feels well. This leads to high risk of recurrence of the disease and the development of severity due to an insufficient treatment. Compliance of the patient is, therefore, a crucial consideration and a key determinant in the successful treatment of COVID regarding both efficacy of the therapy and prevention of recurrence. Long duration regimens, complex dosing schemes, poor understanding of the patient of how or why to adhere to the recommended regimen as well as rapid perception of wellness induce the patient to discontinue the therapy prematurely.
Therefore, it is a further need to provide the combinations which allow an Antiviral therapy that is not only effective, well-tolerated, prevents recrudescence, but also improves patients' compliance. The latter is achieved best if the treatment is simple and of short duration.
According to an embodiment of the present invention, a combination of Artesunate and Mefloquine has been found that it provides a simple fixed-dose treatment administered one to two times a day for 3-10 days. This combination is unexpectedly well tolerated with a low rate of side-effects, and equally high curerates than in comparable treatments. Due to the simple dosing regimen the patients' compliance is excellent.
As used herein the term “fixed-dose” means daily dosage of both antiviral that are same every day for a given treatment course, wherein the amount of the effective dose can be individually determined by the medical practitioner.
According to an embodiment of the present invention, a method for the treatment of SARS-CoV2 in a 3-10 day course is also provided administering a therapeutically effective amount of the combination of Artesunate and Mefloquine is provided, wherein the dosage of Artesunate and Mefloquine for each day remains the same.
The amount of the combination of Artesunate and Mefloquine required to be effective as an antiviral will, of course, vary and is ultimately at the discretion of the medical practitioner. The factors to be considered include the nature and severity of the SARS-CoV2 infection to be treated, route of administration, high or low transmission area, the immune status of the patient as well as age and weight of the patient.
According to an embodiment, the present invention provides a pharmaceutical composition for treatment of SARS-CoV2 with existing pharmaceutical APIs and salts in novel composition, the respective raw materials, pharmaceutically acceptable carrier and an extract can be prepared as granules, tablets, capsules, oral liquid, or mixture pellets.
According to an embodiment of the present invention, the pharmaceutical composition can be a tablet, carrier as lactose or corn starch, magnesium stearate lubricants are added when required, mixed well, and then tableted.
According to another embodiment of the present invention, when the present invention is made in capsules, the powder is filled in required doses in the capsule shells to form capsules.
In accordance with an embodiment of the present invention, wherein when the amount of artesunate is 20-1000mg then the amount of mefloquine is 50-1500mg.
In accordance with an embodiment of the present invention, wherein when the amount of artesunate is 20-550mg, preferably 100-200mg then the amount of mefloquine is 100-750mg, preferably 100-500mg.
In accordance with an embodiment of the present invention, wherein the amount of artesunate is lOOmg then the amount of mefloquine is 200mg.
In accordance with an embodiment of the present invention, wherein the amount of artesunate is 200mg then the amount of mefloquine is 200mg.
In accordance with an embodiment of the present invention, wherein the pharmaceutical composition is also used in the treatment of Hepatitis B, Hepatitis C and Chikungunya virus. Since other modifications and changes varied to fit particular operating requirements and environments are apparent to those skilled in the art, the invention is not considered limited to the example chosen for purposes of disclosure, and covers all changes and modifications which do not constitute departures from the true spirit and scope of this invention.
The description of the present disclosure uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The above are merely exemplary and illustrative of the inventive concept by, one of ordinary skill in the art in the specific embodiments described to make various modifications or additions, or a similar alternative manner, without departing from the invention. The invention, as defined in this disclosure or beyond the scope of the claims, should belong to the scope of the present invention.
Further the dosage of the pharmaceutical composition in the present invention can carry out suitable variation according to the dosage form difference of administration object, route of administration or medicine, but take, guarantees that this pharmaceutical composition can reach effective blood drug level as prerequisite in mammalian body.
While specific language has been used to describe the invention, any limitations arising on account of the same are not intended. As would be apparent to a person skilled in the art, various working modifications may be made to the method in order to implement the inventive concept as taught herein.
The figures and the foregoing description give examples of embodiments. Those skilled in the art will appreciate that one or more of the described elements may well be combined into a single functional element. Alternatively, certain elements may be split into multiple functional elements. Elements from one embodiment may be added to another embodiment. For example, order of processes described herein may be changed and are not limited to the manner described herein. Moreover, the actions of any flow diagram need not be implemented in the order shown; nor do all of the acts need to be necessarily performed. Also, those acts that are not dependent on other acts may be performed in parallel with the other acts. The scope of embodiments is by no means limited by these specific examples.

Claims

WE CLAIM:
1. A pharmaceutical composition for treating Covid- 19 virus comprising a therapeutically effective amount of: an artesunate or its pharmaceutically acceptable salts thereof; and a mefloquine or its pharmaceutically acceptable salts thereof;
2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises the artesunate in the ratio of 0.25% to 66% w/v.
3. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises the mefloquine in the ratio of 0.25%to 90% w/v.
4. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises at least one of pharmaceutically acceptable excipient.
5. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises at least one of pharmaceutically acceptable carrier.
6. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is a granule, tablet, capsule, oral, liquid, or mixture pellets.
7. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition can be administered as oral, parental, topical or any other mode of administration. The pharmaceutical composition as claimed in claim 1, wherein when the amount of artesunate is 20-1000mg then the amount of mefloquine is 50- 1500mg. The pharmaceutical composition as claimed in claim 1, wherein when the amount of artesunate is 20-550mg, preferably 100-200mg then the amount of mefloquine is 100-750mg, preferably 100-500mg. The pharmaceutical composition as claimed in claim 1, wherein the amount of artesunate is lOOmg then the amount of mefloquine is 200mg. The pharmaceutical composition as claimed in claim 1, wherein the amount of artesunate is 200mg then the amount of mefloquine is 200mg. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is also used in the treatment of Hepatitis B, Hepatitis C and Chikungunya virus. A combined preparation comprising: one or more dosage units of an artesunate or its pharmaceutically acceptable salts thereof; and a mefloquine or its pharmaceutically acceptable salts thereof.
PCT/IB2021/050439 2020-12-09 2021-01-21 A pharmaceutical composition of artesunate and mefloquine and method thereof WO2022123323A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003075927A1 (en) * 2002-02-13 2003-09-18 Mepha Ltd. Pharmaceutical combination of artesunate and mefloquine for therapy of malaria

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003075927A1 (en) * 2002-02-13 2003-09-18 Mepha Ltd. Pharmaceutical combination of artesunate and mefloquine for therapy of malaria

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