DESC:[001] FIELD OF THE INVENTION

[002] The present invention is directed to a pharmaceutical composition comprising (a) molnupiravir and (b) 2-deoxy-d-glucose (2DG) for use in treatment or prophylaxis of an infection with a coronavirus, preferably with a coronavirus SARS-CoV-2, or a disorder related to such an infection, preferably COVID-19. The present invention is also further directed to the process for preparation of a pharmaceutical composition comprising (a) molnupiravir and (b) 2-deoxy-d-glucose (2DG).

[003] BACK GROUND OF THE INVENTION

[004] Coronaviruses (CoVs) are enveloped, positive single stranded RNA viruses of Coronaviridae family and the order Nidovirales, and are considered the largest positive RNA viruses, with genomes ranging from 27 to 32 kb. Coronaviruses are the cause of a variety of diseases in humans and animals, which are capable of adapting to new environments through mutation and recombination, and are programmed to alter host range and tissue tropism.

[005] Coronaviruses are phylogenetically subdivided into four genera a, ß, ? and d. Coronaviruses cause infections in humans, and infections in humans are Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The Coronavirus epidemic started in the Chinese city of Wuhan at the turn of the year 2019 and 2020, which is attributed to a previously unknown coronavirus, which was given the preliminary names nCoV-2019 or Wuhan Human Coronavirus (WHCV); later the virus given the official name SARS-CoV-2.

[006] Typical symptoms of SARS-CoV-2 caused virus infection, also referred to as COVID-19 disease (Coronavirus disease 2019) include fever, cough, shortness of breath, pneumonia and gastrointestinal symptoms (e.g. diarrhoea). Severe illness can lead to a respiratory failure that requires mechanical ventilation and support in an intensive care unit. On Jan 30, 2020, the World Health Organization (WHO) declared a global health emergency over the novel coronavirus outbreak. On March 11, 2020 the WHO declared COVID-19 a pandemic, pointing to over 118,000 cases of the coronavirus illness over 110 countries and territories around the world and the sustained risk of further global death. By the end of August 16, 2021 there were more than 207,173,086 confirmed cases of a SARS-CoV-2 infection, spreading across almost every country in the world, with more than 4,360,000 associated deaths.

[007] At present, Remdesivir in the form of injectable dosage form is approved by USFDA for the treatment of coronavirus disease 2019 (COVID-19) requiring hospitalization.

[008] At present, no oral composition is present for the treatment of coronavirus disease 2019. Therefore, there exists a need to develop a pharmaceutical composition as an oral dosage form used for the treatment or prophylaxis of an infection with a coronavirus, preferably with a coronavirus SARS-CoV-2, or a disorder related to such an infection, preferably COVID-19.

[009] SUMMARY OF THE INVENTION

[010] In one aspect the present invention relates to a method of treating SARS-CoV-2 infection in a patient, wherein the method comprises co-administering to said patient
(a) a therapeutically effective dose of molnupiravir and
(b) a therapeutically effective dose of 2-deoxy-d-glucose (2DG).

[011] In another aspect the present invention also further relates to a pharmaceutical composition comprising (a) molnupiravir and (b) 2-deoxy-d-glucose (2DG) for use in treatment or prophylaxis of an infection with a coronavirus, preferably with a coronavirus SARS-CoV-2, or a disorder related to such an infection, preferably COVID-19.

[012] DETAILED DESCRIPTION OF THE INVENTION

[013] The present invention provides methods of treating SARS-CoV-2 infection in a patient, by administering a therapeutically effective dose of molnupiravir in combination with therapeutically effective dose of 2-deoxy-d-glucose (2DG).

[014] In one embodiment of the invention, the present invention provides a method of treating SARS-CoV-2 infection in a patient, wherein the method comprises co-administering to said patient
(a) a therapeutically effective dose of molnupiravir and
(b) a therapeutically effective dose of 2-deoxy-d-glucose (2DG).

[015] In another embodiment of the invention, the present invention provides a pharmaceutical composition comprising (a) molnupiravir and (b) 2-deoxy-d-glucose (2DG) for use in treatment SARS-CoV-2 infection.

[016] In one specific embodiment of the invention, the present invention provides an oral pharmaceutical composition comprising (a) molnupiravir and (b) 2-deoxy-d-glucose (2DG) for use in treatment SARS-CoV-2 infection.

[017] In further embodiment of the invention, the present invention relates to the combination of (a) molnupiravir and (b) 2-deoxy-d-glucose (2DG).

[018] In another specific embodiment of the invention, the present invention provides an oral pharmaceutical composition comprising (a) molnupiravir and (b) 2-deoxy-d-glucose (2DG);
wherein the oral pharmaceutical composition is in the dosage form of oral granules, dispersible tablets, conventional tablets, capsules, orally disintegrating tablets, syrup, suspension, or emulsion.

[019] In accordance with the methods of the invention, molnupiravir can be co-administered in combination with 2DG. Without intending to be bound by any particular mechanism or effect, such co-administration can in some cases provide one or more of several unexpected benefits including
i) Co-administration of molnupiravir and 2DG has a synergistic effect for the treatment of coronavirus SARS-CoV-2, preferably by induction of viral death.
ii) Co-administration of molnupiravir and 2DG provides a better therapeutic result than administration of the single agent alone.
iii) Co-administration of molnupiravir and 2DG increases the sensitivity of viral cells, allowing lower doses of each molnupiravir or 2DG to be administered to the patient.

[020] In one embodiment of the invention, molnupiravir is administered at a daily dose of about 0.5 mg to about 500 mg per kg weight of the patient. In specific embodiment, preferably molnupiravir is administered at a daily dose of about 1 mg to about 250 mg per kg weight of the patient.

[021] In another embodiment of the invention, 2DG is administered at a daily dose in the range of about 1 mg to about 1g per kg body weight of the patient. Further 2DG is more specifically administered in a daily dose of about 1 mg to about 500 mg per kg body weight of the patient. In another embodiment, the therapeutically effective dose is a daily dose of about 10 mg to about 400 mg per kg body weight of the patient to be treated.

[022] In another embodiment of the invention, the present invention provides a method of treating SARS-CoV-2 infection in a patient, wherein the method comprises co-administering to said patient
(a) a therapeutically effective dose of molnupiravir, wherein a therapeutically effective dose of molnupiravir is obtained by orally administering molnupiravir in a range of about 0.5 mg to about 500 mg per kg body weight of a patient, and
(b) a therapeutically effective dose of 2-deoxy-d-glucose (2DG), wherein a therapeutically effective dose of 2DG is obtained by orally administering 2Dg in a range of about 1 mg to about 1 g per kg body weight of a patient.

[023] In one embodiment of the invention the combination of molnupiravir and 2DG is administered twice a day or once a day, once every third day, or once a week for the treatment of coronavirus SARS-CoV-2 infection.

[024] In another embodiment of the invention, the combination of molnupiravir and 2DG is administered for period of at least one day, two days, three days, four days and five days. In a further embodiment of the invention, the combination of molnupiravir and 2DG shall be administrated for a period of at most one month, more preferably for a period of at most 15 days.

[025] In one embodiment of the invention the combination of molnupiravir and 2DG of the present invention is administered by oral administration. Molnupiravir and 2DG used in the present invention may be in crystalline, amorphous, micronized form or nonmicronized form. The D90 particle size of molnupiravir and 2DG is in the range of about 0.1µm to about 1000µm.

[026] In embodiment of the invention the combination of molnupiravir and 2DG shall be administered orally as such or with an inert diluent or with an assimilable carrier, or it can be enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or suspended in a liquid or gel, or incorporated directly with the food of the diet. For oral therapeutic administration, combination of molnupiravir and 2DG can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, powders or granules or blend for suspensions, syrups and the like. Such compositions and preparations contain enough of the active agent molnupiravir and 2DG to deliver the therapeutically active doses described above. The tablets, troches, pills, capsules, and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose or gelatin; excipients such as dicalcium phosphate, microcrystalline cellulose, sorbitol, mannitol, dextran and lactose monohydrate; a disintegrating agent such as corn starch, potato starch, alginic acid, sodium starch glycolate, croscarmellose sodium and the like; a glidant selected from colloidal silicon dioxide, a lubricant such as magnesium stearate and sodium stearyl fumarate; a sweetening agent such as saccharin, sucralose and natural sweeteners; and/or a flavoring agent such as peppermint, lemon, orange, strawberry and any natural or artificial fruit flavours, oil of wintergreen, or cherry flavoring and/or a colouring agent such as sunset yellow. When the dosage unit form is a capsule, it can contain, in addition to materials of the above types, a liquid carrier. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules can be coated with shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinyl acetate. A syrup or elixir can contain the active compounds of molnupiravir and 2DG, a sweetening agent, methyl and propylparabens as preservatives, and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.

[027] The present invention provides a pharmaceutically acceptable formulation comprising a combination of molnupiravir and 2DG useful in the methods of the present invention. In one embodiment, the formulation is crystalline, amorphous or granular in nature, and the molnupiravir and 2DG is packaged in a sachet for later decantation into a potable liquid for oral administration to the patient. In this embodiment, the liquid can be a syrup or, more conveniently, a commonly consumed liquid, such as water or fruit juice. Usually, the liquid used to dissolve, dilute, or suspend combination of molnupiravir and 2DG in a formulation is water. In another embodiment, the molnupiravir and 2DG is formulated as an immediate release or disintegrating or dispersible tablet or pill or as granules, powder or blend filled into sachet containing an amount in the range of about 10 mg to about 110 g. In some embodiments, each immediate release or disintegrating or dispersible tablet or pill or as granules, powder or blend filled into sachet contains about 100 mg to about 5 g of molnupiravir and 2DG. In one embodiment, each immediate release or disintegrating or dispersible tablet or pill or as granules, powder or blend filled into sachet containing 200 mg of molnupiravir and 2.34 g of 2DG, 400 mg of molnupiravir and 2.34 g of 2DG and 800 mg of molnupiravir and 2.34 g of 2DG.

[028] The following examples are provided to illustrate the present invention. It is understood, however, that the invention is not limited to the specific conditions or details described in the examples below. The examples should not be construed as limiting the invention as the examples merely provide specific methodology useful in the understanding and practice of the invention and its various aspects. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modification to the disclosed embodiments can occur to those who are skilled in the art.

[029] Example 1:

[030] Oral Powder Composition comprising molnupiravir and 2DG

S. No Ingredients mg/Sachet
1. Molnupiravir 800
2. 2-deoxy-d-glucose 2340
3. Sorbitol 88.30
4. Colloidal silicon dioxide 34
5. Sucralose 102
6. Orange flavour 34
7. Sunset yellow 1.7
Total 3400

[031] Process for Preparation:

[032] Molnupiravir, 2-deoxy-glucose, sorbitol, sucralose, orange flavour, sunset yellow are thoroughly mixed and further mixed with colloidal silicon dioxide to form the final powder which was filled into sachets.
,CLAIMS:1. A combination comprising
a) molnupiravir and
b) 2-deoxy-d-glucose (2DG)

2. An oral pharmaceutical composition comprising
a) molnupiravir and
b) 2-deoxy-d-glucose (2DG).

3. The oral pharmaceutical composition as claimed in claim 1, wherein the composition is in form of dosage form selected from group consisting of oral granules, oral powder, dispersible tablets, conventional tablets, capsules, orally disintegrating tablets, syrup, suspension and emulsion.

4. The oral pharmaceutical composition as claimed in claim 3, wherein the composition is oral granules or oral powder.

5. The oral pharmaceutical composition as claimed in claim 4, wherein the oral granules or oral powder are filled into sachets.

6. The oral pharmaceutical composition as claimed in claim 4, wherein sachet contains of about 200 mg of molnupiravir.

7. The oral pharmaceutical composition as claimed in claim 4, wherein sachet contains of about 400 mg of molnupiravir.

8. The oral pharmaceutical composition as claimed in claim 4, wherein sachet contains of about 2.34 g of 2-deoxy-d-glucose (2DG).

9. The oral pharmaceutical composition as claimed in claim 2, wherein D90 particle size of molnupiravir is 0.1µm to 1000µm.

10. The oral pharmaceutical composition as claimed in claim 2, wherein D90 particle size of 2-deoxy-d-glucose (2DG) is 0.1µm to 1000µm.