WO2021201805A1

WO2021201805A1 - Niclosamide compositions with high solubility and bioavailability

Info

Publication number: WO2021201805A1
Application number: PCT/TR2021/050293
Authority: WO
Inventors: Mehmet Nevzat PISAK
Original assignee: Imuneks Farma Ilac San. Ve Tic. A.S.
Priority date: 2020-04-01
Filing date: 2021-03-31
Publication date: 2021-10-07
Also published as: TR202006655A2; TR202005165A2

Abstract

The present invention is based on the unexpected discovery that highly soluble and bioavailable niclosamide compositions can be made at a commercial scale with a simple manufacturing process. Accordingly, the present invention provides an oral composition comprising niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates or esters, at least one emulsifier, at least one dextrin compound and at least one alkalizing agent.

Description

NICLOSAMIDE COMPOSITIONS WITH HIGH SOLUBILITY AND

BIOAVAILABILITY

TECHNICAL FIELD

The present invention provides an oral composition comprising niclosamide or a pharmaceutically acceptable derivatives such as salts, hydrates or esters, solving the solubility and bioavailability problems in the prior art with a simple manufacturing process.

BACKGROUND ART

Niclosamide, or 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide, is an efficacious, minimally toxic and FDA-approved anti-helminth drug that has been used in patients for decades The anti-parasitic activity of niclosamide was originally reported to be mediated by inhibition of mitochondria oxidative phosphorylation and anaerobic ATP production [Weinbach, 1969].

There has been increased interest in niclosamide's action against key pathological pathways due to the fact that niclosamide not only inhibits the Wnt/p-catenin, mTORCl, STAT3, NF-KB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. (Li et al., Cancer lett (2014)10;349(1):8-14) Thus, the use of niclosamide is suitable for almost all types of cancer. Niclosamide has also shown great potential for the treatment of viral diseases and was found to be effective against various viral infections such as SARS-CoV, MERS-CoV, ZIKV, HCV, and human adenovirus, indicating its potential as an antiviral agent and also holds great potential for the treatment of COVID-19. (Xu et al, 2020, “Broad Spectrum Antiviral Agent Niclosamide and its therapeutic Potential”)

Luo et al, published an article in Journal of Medical Virology on 22 January 2020 about global health concerns stirred by emerging viral infections saying; “Emerging viral infections continue to pose a major threat to global public health. In 1997, a highly pathogenic avian influenza A (H5N1) virus was found to directly spread from poultry to humans unlike previously reported, other avian influenza A vims subtypes (H7N9, H9N2, and H7N3) were also associated with human disease, raising an alarm that all subtypes of influenza A vims circulating in domestic and wild birds and livestock can potentially spill over to humans, resulting in pandemics. The outbreak of severe acute respiratory syndrome (SARS) happened during 2002 to 2003 in China was caused by a novel coronavirus (CoV) designated SARS-CoV, spreading to 37 countries and resulting in more than 8000 infections and 774 deaths (9.6% mortality rate).6 More recent years have witnessed the emergence of several other important viral diseases, including a pandemic influenza caused by a swine H1N1 influenza A virus in 2009, the Middle East respiratory syndrome (MERS) caused by a new deadly (>30% mortality) MERS-CoV in 2012, the Ebola outbreak in West Africa during 2014 to 2016, and the microcephaly crisis associated with Zika virus infection in 2015.”

Coronaviruses (CoVs) are enveloped and positive- sense single- stranded RNA viruses belonging to the family Coronaviridae within the order Nidovirales. Human coronavirus infections are typically mild and rarely associated with severe diseases. However, the epidemics of Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) caused alarming morbidity and mortality. While coronaviruses are often zoonotic, person-to-person transmission has been confirmed for SARS- CoV-2, similar to MERS-CoV and SARS-CoV.

“Now, tens of thousands of people have been infected with the newly identified CoV termed 2019-nCoV. The airborne and person-to-person spread of the 2019-nCoV have been the major routes of transmissions, as demonstrated by new infections among family members, health care providers, and communities.” said in the Article of Lou et al. The infection causes multiple deaths and an extreme financial burden for the global economy.

Thus, it is of grave importance to develop new therapies for the treatment of viral diseases, especially viral RNA infections including SARS-CoV, MERS-CoV, ZIKV, HCV and most importantly 2019-nCoV, which has become a global pandemic.

Features, evaluation and treatment of coronavirus Covid-19 are explained in detail on March 20, 2020 of StatPearls Publishing by Cascella M. et al. (PMID: 32150360)

Despite showing very high promise and chosen among thousands of molecules for cancer and viral diseases as a prime candidate. The use of niclosamide has a major disadvantage as an anti viral or anti-cancer agent; low solubility, low bioavailability and poor pharmacokinetic profile, which results in limited efficacy as a therapeutic for human use in these indications. As an example, the clinical trial of niclosamide for prostate cancer was based on several preclinical models of castration resistant prostate cancer and niclosamide was shown to be a potent anti-neoplastic agent. (PLos One, 2018 August 15;13(8):e0202709) All of the results demonstrated decreased cancer cell proliferation across multiple cell lines. Due to the promising in-vitro results, one would expect, at least a moderate level of success. But in the words of the principal investigator of the study: “Because niclosamide plasma concentrations in the maximal tolerated dosing cohort (i.e., 500 mg TID) were below those expected to exert an anti-tumor effect, the study was closed for futility.” Which creates another problem to be solved; niclosamide can create side effects when administered for a long period of time. Thus, the dose cannot surpass 2000mg a day, or even 1500mg a day as mild symptoms start occurring even at this daily dose level.

Thus, the effectiveness of niclosamide as a potential therapeutic is hindered by its low low solubility and dissolution consequently leading to low bioavailability. Thus, very high oral doses and repeated dosing have to be used to obtain effective blood concentrations, but which creates toxicity and other side effects such as Nausea, Anorexia, Vomiting, Diarrhea, Weight loss, Lipase elevation, Colitis, and Abdominal pain.

There have been multiple studies to overcome the solubility and bioavailability problems of niclosamide in the state of the art, some of which include the use of formulation technologies such as liposomes, niclosamide complexes with emulsifying agents and other compounds such as cyclodextrins.

The use of cyclodextrins in order to increase the solubility of Niclosamide is studied in the art. Yang et. al, in their study (2005 “Effect of 4-Sulphonato-Calix[n]Arenes and cyclodextrins on the solubilization of niclosamide, a poorly water soluble anthelmintic”) disclose the use of high levels of cyclodextrins with niclosamide to form complexes of niclosamide: cyclodextrin at a minimum ratio of 1:0,25 with the use of 4-Sulphonato-Calix[n]Arenes, which in the words of Yang et al “creates an additive effect rather than a synergistic one”. Furthermore, cyclodextrins are expensive excipients and the use of cyclodextrins can be toxic at high volumes.

Rehman et al, (2017 “Fabrication of Niclosamide loaded solid lipid nanoparticles: in vitro characterization and comparative in vivo evaluation”) have studied solid nano particle formulations of niclosamide by formulating niclosamide with stearic acid, tween 80 and PEG 400. The issue with this formulation is that stearic acid is acidic and actually decreases the solubility of niclosamide which is increased by tween 80 and PEG-400. Because, Rehman et al have not conducted the study with a combination excluding stearic acid, the increase in solubility is falsely attributed in part to the use of stearic acid. Furthermore this formulation has to be freeze dried, which is a complex manufacturing technology requiring expensive manufacturing equipment and people with significant experience to oversee the production process.

Thus, there is still a need in the art for a pharmaceutical composition enhancing the solubility and the bioavailability of niclosamide, which is also stable, easy to manufacture and economically more viable, so it can be mass produced with ease in situations like the 2019- nCoV pandemic.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising; preferably encapsulating niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates or esters, solving the solubility and bioavailability problems of niclosamide in the prior art with a simple manufacturing process.

The present invention provides a pharmaceutical composition comprising niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates or esters, at least one emulsifier and at least one dextrin compound.

In one aspect, the present invention relates to a pharmaceutical composition comprising niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates or esters, at least one emulsifier, at least one alkalizing agent and a dextrin.

In another aspect, the present invention provides a pharmaceutical composition comprising a niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates or esters with at least one emulsifier having a HLB value between 10 and 25 and at least one alkalizing agent, and preferably one dextrin compound.

In another aspect, the present invention provides a pharmaceutical composition comprising a niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates or esters with at least one emulsifier having a HLB value between 10 and 25, at least one alkalizing agent and a dextrin compound, preferably maltodextrin, beta-cyclodextrin or a derivative thereof. In another aspect, the emulsifier is preferably selected from the group consisting of polyoxethylene derivatives, diethylene glycol mon ethyl ether, sorbitan esters, polyethylene glycol derivatives and a combination thereof. Polyoxethylene can be polyoxyglycerides such as stearoyl polyoxyl-32 glycerides, lauroyl polyoxyl-32 glycerides or polyoxy-ethylene sucrose diester dimyristate, Polyoxy- ethylene sucrose diester dinnyristate, polyoxy-ethylene sucrose diester dipalmitate, polyoxy-ethylene sucrose diester dioleate; sorbitan esters can be polysorbate 80, polysorbate 60, polysorbate 20; polyethylene glycol derivatives can be PEG-8 laurate, PEG 400 monoluarate, PEG 10 isooctylphenyl ether, PEG 40 stearate, PEG 50 stearate, PEG 40 isooctylphenyl ether, and others selected from sodium stearoyl-2-lactylate, sodium stearoyl lactylate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an oral pharmaceutical composition comprising niclosamide or a pharmaceutically acceptable derivatives thereof, at least one emulsifier and at least one dextrin compound.

The present invention also relates to an oral composition comprising niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates or esters, at least one emulsifier, at least one dextrin compound and at least one alkalizing agent.

The emulsifier of the present invention has an HLB value between 10 and 25, preferably between 10 and 21.

As used herein, HLB means hydrophilic-lipophilic balance (HLB), i.e. the balance of the size and strength of the hydrophilic (water-loving or polar) and the lipophilic (oil-loving or non-polar) groups of the emulsifier. In the HLB system, each emulsifier is assigned a numerical value which is called its HLB . The HLB of emulsifiers is shown in all current ICI emulsifier literature, and similar values may be calculated or estimated by various means for any emulsifier. All emulsifiers consist of a molecule that combines both hydrophilic and lipophilic groups. An emulsifier that is lipophilic in character is assigned a low HLB number (below 9.0), and one that is hydrophilic is assigned a high HLB number (above 10.0). Those in the range of 9-11 are intermediate.

According to the present invention, the emulsifier is selected from, but not limited to the group consisting of PEG-7 Glyceryl Cocoate, PEG-20 Almond Glycerides, PEG 40 Sorbitane Hexaoleate, PEG 40 Sorbitane Perisostearate, PEG 10 Olive Glycerides, PEG-8 caprylic/capric glycerides (Labrafac CM 10 - Gattefosse), Polyoxyethylene oleyl ether (EMULGEN 408 - EMULGEN 430), PEG Sorbilate Hexa oleate, Polysorbate 65 PE(20) sorbitan tristearate, Polyoxyethylene lauryl ether (G-3705), Polyoxyethylene lauryl ether (EMULGEN 106 - EMULGEN 108 - EMULGEN 109P - EMULGEN 120 - EMULGEN 123P - EMULGEN 147 - EMULGEN 150), PEG 25 Hydrogenated Castor Oil, Polyoxyethylene monostearate (Myrj 45), PEG 7 Glyceryl Cocoate (Sympatens-GMC/070), Glyceryl Stearate, PEG- 100 Stearate Polysorbate 85, PEG-7 Olivate, PEG-20 sorbitan trioleate (Tween-85 Atlas/ICI), PEG-20 sorbitan tristearate (Tween 65 Atlas/ ICI), PEG-25 hydrogenated castor oil (Simulsol 1292 Seppic) (Cerex ELS 250 Auschem SpA), PEG-25 trioleate (Tagat TO Goldschmidt), Polysorbate 85, PEG 8 Stearate, PEG 400 Monoleate, PEG Sorbitan Tetraoleate, PEG 400 Monoleate Polyoxyethylene monooleate, PEG-8 Oleate, PEG 400 Monostearate, PEG 400 Monostearate Polyoxyethylene monostearate Polyoxy-Ethylene Sucrose diester (Diemcat), PEG 35 Almond Glycerides, PEG 15 Glyceryl Isostearate, Polyoxyethylene alkyl phenol (Igepal Ca-630), PEG-35 castor oil (Cremophor EL /Cremophor EL-P BASF), Methyl-oxirane polymer with oxirane (Pluronic L-64 BASF), Polyoxyethylene alkyl ether (EMULGEN 707 - EMULGEN MS-110- EMULGEN 709 - EMULGEN LS-110 - EMULGEN 1108 - EMULGEN LS-114 - EMULGEN 1118S-70 - EMULGEN 1135S-70 - EMULGEN 1150S-60), Polyglyceryl-3 Methyglucose Distearate = 12 Oleth-10 Oleth-10 / Polyoxyl 10 Oleyl Ether NF /(PEG 10 Oleyl Ether), PEG 8 Isooctylphenyl Ether, PEG 10 Stearyl Ether, PEG 35 Castor Oil, Polyethylene glycol 400 monolaurate, Polyoxyethylene distyrenated phenyl ether (EMULGEN A-60 - EMULGEN A-90 - EMULGEN A-500), PEG 10 Cetyl Ether, PEG 40 Castor Oil, PEG- 8 Laurate, Acconon C-50 (PEG-32 Hydrogenated Palm Glycerides /EP/NF Stearoyl Macrogolglycerides (EP) / Stearoyl Polyoxylglycerides (NF) / Stearoyl polyoxyl-32 glycerides, PEG-35 hydrogenated castor oil (Cremophor RH40 BASF) , PEG-40 hydrogenated castor oil (Cremophor RH40 BASF), PEG- 1000 succinate (tocophersolan, D-a-tocopheryl/ TPGS - Eastman), Polyoxyl-40-hydrogenated castor oil (Cremophor RH 40 BASF), Polyoxyethylene hydrogenated castor oil 40 (HCO-40 Nikkol), PEG 400 Monoluarate (Polyoxyethylene monolaurate), Polyoxyethylene sorbitan mono-oleate (Tween 80), Polyoxyethylene derivatives (EMULGEN B-66), PEG 10 Isooctylphenyl Ether, Polyoxyethylene cetyl ether (EMULGEN 220) , Polysorbate 60 PE(20) sorbitan monostearate, PEG 12 Tridecyl Ether ,PEG 18 Tridecyl Ether ,PEG 40 Hydrogenated Castor Oil, Acconon C-44 (polyoxyethylene 32 lauric glycerides /PEG-32 Lauric Glycerides/ Lauroyl Macrogolglycerides (EP)/ Lauroyl Polyoxyglycerides (NF) /Lauroyl Polyoxyl-32 glycerides, PEG-60 hydrogenated castor oil (HCO-60 - Nikko) , PEG-8 caprylic/capric glycerides (Labrasol - Gattefosse), Polysorbate 60 NF ,Poloxyethylene sorbitan monostearate, Polysorbate 60, PEG-60 Almond Glycerides, PEG 20 Glyceryl Stearate, PEG 20 Stearate , PEG-20 Methyl Glucose Sesquistearate , Polysorbate 80, PEG-20 sorbitan monooleate (Tween-80 Atlas/ICI), Polyoxyethylene sorbitan monooleate, Polisorbate 60 (PS 60), Polyoxyethylene sorbitan monolaurate (Tween 20) , Polysorbate 80, PEG 20 Stearyl Ether, PEG 20 Oleyl Ether, Polysorbate 80 PE(20) sorbitan monooleate, PEG 20 Cetyl Ether, PEG (20) Hexadecyl Ether, PEG 60 Hydrogenated Castor Oil, PEG 30 Stearate, PEG 75 Lanolin, Polysorbate 20, Polysorbate 20 NF, Polyoxyethylene lauryl ether (Brij 35) , Polysorbate 20,Eumulgin® L (PPG-l-PEG-9 Lauryl Glycol Ether/ Glycols, 1,2-, 02-16, ethoxylated propoxylated) ,PEG 23 Lauryl Ether, PEG-20 sorbitan monolaurate (Tween20 Atlas/ICI), Polyoxy- Ethylene Sucrose diester Dimyristate, PEG 40 Stearate, Polyoxy- Ethylene Sucrose diester Dinnyristate, Polyoxy- Ethylene Sucrose diester Dipalmitate ,PEG 50 Stearate ,PEG 40 Isooctylphenyl Ether, Polyoxy-Ethylene Sucrose diester Dioleate, Polyoxyethylene- polyoxypropylene copolymers (Pluronic F 127 - BASF) ,PEG 100 Stearate, Polyoxyethylene myristyl ether (EMULGEN 4085), PEG-80 Sorbitan Laurate Linoleamide DEA, Stearamide MEA, Cetearyl Glucoside, Triethanolamine oleate , Sucrose monostearate, Oleth- 10 / Polyoxyl 10 Oleyl Ether NF, Steareth-10, Ceteth-10, Cocamide MEA, Isosteareth-20, Sucrose laurate, Sucrose stearate, Lauramide DEA, Stearic Acid, Ceteareth-20, Oleth-20, Steareth-20, Steareth-21, Cetearyl Alcohol , Ceteth-20 , Isoceteth-20 ,Ceteth-20, Sucrose palmitate, Laureth- 23, Sodium oleate 16.9, Potassium oleate, Steareth-100, Sodium stearoyl-2-lactylate , Sodium stearoyl lactylate and a combination thereof.

The emulsifier is preferably selected from the group consisting of polyoxethylene derivatives, sorbitan esters, polyethylene glycol derivatives and a combination thereof. Polyoxethylene can be polyoxyglycerides such as stearoyl polyoxyl-32 glycerides, lauroyl polyoxyl-32 glycerides or polyoxy-ethylene sucrose diester dimyristate, Polyoxy- ethylene sucrose diester dinnyristate, polyoxy-ethylene sucrose diester dipalmitate, polyoxy-ethylene sucrose diester dioleate; sorbitan esters can be polysorbate 80, polysorbate 60, polysorbate 20; polyethylene glycol derivatives can be PEG- 8 laurate, PEG 400 monoluarate, PEG 10 isooctylphenyl ether, PEG 40 stearate, PEG 50 stearate, PEG 40 isooctylphenyl ether, PEG-25 Castor Oil, PEG-30 Castor Oil, PEG-40 Castor Oil, PEG-25 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, Hexylene Glycol with PEG-25 Hydrogenated Castor Oil (and) PEG-40 Hydrogenated Castor Oil. The emulsifier is preferably polyoxylglycerides or polysorbates or polyethylene glycol derivative. Thus, the emulsifier used in the present composition is preferably selected from; polysorbate 80, polysorbate 60, polysorbate 20, stearoyl polyoxyl-32 glyceride (Acconon C- 50/ Gelucire 50/13) or lauroyl polyoxyl-32 glyceride (Acconon C-44/ Gelucire 44/14), PEG-8 laurate, PEG 400 monoluarate, PEG 10 isooctylphenyl ether, PEG 40 stearate, PEG 50 stearate, PEG 40 isooctylphenyl ether, PEG-25 Castor Oil, PEG-30 Castor Oil, PEG-40 Castor Oil, PEG- 25 Hydrogenated Castor Oil, PEG-6Hydrogenated Castor Oil, Hexylene Glycol with PEG-25 Hydrogenated Castor Oil (and) PEG-40 Hydrogenated Castor Oil.

Although substantially higher levels of solubility compared to prior art can be achieved with the composition of the present invention comprising an emulsifier and a dextrin compound such as a sorbitan ester (polysorbate 80), beta-cyclodextrin or maltodextrin ; it has also been surprisingly discovered that adding an alkalizing agent such as sodium bicarbonate results in this synergistic highly soluble, niclosamide composition.

Thus, the pharmaceutical composition of the present invention will preferably further comprise an alkalizing agent.

Alkalizing agents are used to increase the pH of pharmaceutical formulations and are also used to treat gastro intestinal symptoms associated with acidity in the gastro intestinal tract, thus the use of an alkalizing agent is twofold within the scope of the present invention, increase the solubility and bioavailability of niclosamide and to decrease the gastro intestinal side effects associated with niclosamide.

The alkalizing agents of the present invention are selected from sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, magnesium carbonate, ammonium carbonate, ammonium bicarbonate, potassium carbonate, potassium bicarbonate, sodium glycine carbonate, disodium glycine carbonate, arginine carbonate, arginine bicarbonate, lysine carbonate, potassium hydroxide, magnesium hydroxide, potassium chloride, sodium hydroxide, potassium hydroxide, ammonium hydroxide, methanolamine, monoethanol amine, propanolamine, arginine, lysine, methylene diamine, ethylene diamine, and propylene diamine. It has been found that the use of an alkalizing agent improves the solubility and bioavailability of niclosamide, not to be limiting the scope of the present invention, it is believed by the inventor that the use of an alkalizing agent has a dual action; pH dependent increase of solubility and more importantly increase gastrointestinal permeability of niclosamide. Furthermore, the addition of an alkalizing agent increases the plasma concentration of niclosamide and provides a more constant plasma concentration for a longer period of time, higher AUC compared to the composition that only entails an emulsifier and a dextrin compound.

According to the present invention, the composition comprises niclosamide in an amount of 5% to 30%, preferably 5% to 25% and more preferably 5% to 20% by total weight of the composition.

Dextrins are a group of low-molecular-weight carbohydrates produced by the hydrolysis of starch or glycogen.

One preferred type of dextrin of the present invention is maltodextrin and the others are cyclodextrins.

Maltodextrin is a short-chain starch sugar used as a food additive in prior art. It is produced also by enzymatic hydrolysis from gelled starch, and is usually found as a creamy-white hygroscopic spray-dried powder. Maltodextrin is easily digestible, being absorbed as rapidly as glucose, and might either be moderately sweet or have hardly any flavor at all.

The cyclical dextrins are known as cyclodextrins. They are formed by enzymatic degradation of starch by certain bacteria, for example, Paenibacillus macerans (Bacillus macerans). Cyclodextrins have toroidal structures formed by 6-8 glucose residues.

The preferred dextrin compounds of the present invention are selected from beta cyclodextrin and derivatives including but not limited to: b-cyclodextrin, 2-hydroxypropyl-P-cyclodextrin, sulfobutylether b-cyclodextrin sodium salt, randomly methylated b-cyclodextrin, branched b- cyclodextrin and maltodextrin.

Although y-cyclodextrin compounds can also be employed, the preferred embodiment of the invention entails the use of beta cyclodextrins including; beta cyclodextrin (BCD), DM-b- cyclodextrin, RM^-cyclodextrin and hydroxypropyl b-cyclodextrin (HPBCD), which have enhanced the solubility of niclosamide even with the least expensive cyclodextrin compound b-cyclodextrin. In addition, formulations in the prior art have focused on extremely high ratios of cyclodextrin compounds such as HPBCD, contrary to the findings of the present invention that provides significantly higher levels of solubility with lower amounts of cyclodextrin compared to state of the art, when combined with emulsifiers that have a high HLB value and an alkalizing agent at specific ratios.

The emulsifier of the present invention preferably has an HLB value between 10 and 25, preferably between 10 and 21.

It has also been surprisingly discovered that polyoxyethylene derivatives and preferably sorbitan esters can have an even stronger effect on the solubility of niclosamide, when combined with a dextrin. The amphiphilic nature of sorbitan esters, combined with their high HLB value, coupled with the hydrophilic nature of dextrins, combined with the permeability and pH modifying effect of an alkalizing agent, results in this synergistic composition with a highly soluble and bioavailable niclosamide composition.

The pharmaceutical composition according to the present invention may further comprise a silica derivative. When the composition of the present invention must be made into powder form; silica derivatives have been found to be the most appropriate medium. The addition of the silica derivative gives the composition of the present invention versatility.

Silica derivatives have been used in oral dosage formulations for decades, there are many different silica derivatives used for various applications (i.e: to increase flowability, compressibility etc.)

The preferred silica derivatives of the present invention have an extremely low bulk density and high surface area. These silica derivatives have a mean particle diameter of 10 to 250 micron (determined according to the laser diffraction method) and a BET surface area of 40 to 400 m2/g (determined according to DIN 66 131 with nitrogen). The silica derivatives also typically have a pore volume of about 0.5 to 2.5 mL/g, wherein less than about 5% of the overall pore volume has a pore diameter of less than about 5 nm, the remainder being mesopores and macropores. Additionally, the silica derivatives typically will have a pH in the range of about 3.4 to about 8, preferably have a tamped (tapped) density of about 50 to 600 g/L and most preferably a tamped density between 50 to 400 g/L and are most preferably hydrophilic (The tapped density is calculated according to ISO 787-11 and converted to the value in g/L).

As used herein, BET surface area means the surface area of a solid in relation to its mass, measured in m²/g. As defined in DIN 66131, it is generally measured based on the BET method (Brunauer, Emmett, Teller, in Journal of the American Chemical Society 60 (1938), p. 309). As used herein, tamped (tapped) density means a measured variable that describes the amount of volume lost by a powdered solid when it is shaken or packed down firmly as defined by ISO 787-11.

The silica derivative of the present invention is preferably selected as calcium silicate (such as Zeopharm) most preferably zeopharm 5170, or magnesium aluminometasilicate (such as Neusillin) most preferably Neusillin US2, or colloidal silicon dioxide, most preferably AEROPERL® 300.

The specific silica material that was used in the studies of the inventions for compositions and methods was AEROPERL® 300 (a hydrophilic silica derivative), which is available from Evonik Degussa AG, Dusseldorf, Germany. However, other silica derivatives that have similar physical and chemical properties described herein can also be used.

In one embodiment of the invention, the particles of the silica derivative have preferably a mean grain diameter of 10-120 microns. In another embodiment of the invention the silica particles have a BET surface area of at least 150 m2/g. In another embodiment of the invention the silica particles have a BET surface area of at least 200 m2/g. In another embodiment of the invention, the silica particles have a BET surface area of at least 250 m2/g. In yet another embodiment of the invention the silica particles have a BET surface area of at least 275 m2/g.

The liquid niclosamide composition is loaded on to the silica derivative with a silica derivative to niclosamide ratio of 0,75:1 to 2:1. preferably with a large surface area and high tamped density, which decreases the amount of silica derivative needed and also increases the amount of niclosamide inclusion complex that can be loaded. Accordingly, in one preferred embodiment, the manufacturing method of the composition entails the mixing of niclosamide with the emulsifier first, before it is mixed with the silica derivative if it is to be made into powder form. Or alternatively another preferred emulsifier of the present invention Acconon C50 can be employed instead of tween 80, in which case the silica derivative will not have to be used, since Acconon C50 is already in solid form.

According to the present invention, the composition comprises an emulsifier or emulsifiers in an amount of between 20 to 95%, preferably 30 to 90% and more preferably 40 to 85% by the total weight of the composition. According to the present invention, the composition comprises at least one alkalizing agent in an amount of between 1 to 40%, preferably 2 to 30% and more preferably 5 to 20% by the total weight of the composition.

According to the present invention, the composition comprises at least one dextrin compound in an amount of between 1 to 50%, preferably 2 to 40% and more preferably 5 to 20% by the total weight of the composition.

As the specific combination of the emulsifier with the dextrin provides improved solubility of niclosamide, their weight ratio is very important. The correct ratio enables the composition to reach the needed solubility and bioavailability to be an effective therapy. Especially when an alkalizing agent is added to the emulsifier and dextrin compound. Accordingly, at least 1000% higher solubility at pH 6.8 (SIF//simulated instestinal fluid) is achieved by the present invention. The increase in the solubility of niclosamide in SIF will also evidently increase the blood concentrations of niclosamide when orally administered to subjects, including warm blooded animals, as evidenced by the results of the pharmacokinetic study below in the example.

In a preferred embodiment, the weight ratio of the dextrin compound to the emulsifier is between 1:1 to 1:20, and preferably between 1:5 to 1:15.

In a preferred embodiment, the weight ratio of niclosamide to the dextrin compound is between 10:1 to 1:2, preferably 5:1, to 1:1.

In a preferred embodiment, the weight ratio of the alkalizing agent to the emulsifier is between 1:1 to 1:40, and preferably between 1:4 to 1:20.

In a preferred embodiment, the weight ratio of niclosamide to the alkalizing agent is between 10:1 to 1:2, preferably 5:1 to 1:3, more preferably 2:1 to 1:2.

In a preferred embodiment, the weight ratio of niclosamide to the emulsifier is between 1:1 to 1:12, preferably 1:3 to 1:10. In order to decrease dysphagia with critically ill patients, the preferred oral dosage forms of the present invention are effervescent tablet, powder or liquid, pellet, granule, solution, suspension or syrup. Specifically, the preferred form of the composition according to the present invention is a liquid oral suspension or in the form of powder to be reconstituted with water. Thus, it can be easily administered to the pediatric population and geriatric population that have swallowing difficulties (dysphagia). Moreover, patients of any age group in the hospital setting, due to the severity of the viral infection or cancer can be easily administered by the composition of the present invention as a liquid suspension with the help of an injector. So, the preferred form of the present invention would also help increase patient compliance.

In another embodiment of the present invention, the oral composition may further comprise at least one pharmaceutically acceptable excipient known by one skilled in the art.

Oral dosage forms of the present invention may comprise suitable diluents, binders, lubricants, antioxidants, disintegrating agents, surfactants, glidants, sweetening agents, coloring agents and coating agents as pharmaceutically acceptable excipients and preferably disintegrant, lubricant and mixture thereof.

Pharmaceutically acceptable diluents of the present invention may be selected from the list comprising magnesium stearate, lactose, microcrystalline cellulose, starch, pre-gelatinized starch, calcium phosphate, calcium sulphate, calcium carbonate, sodium starch glycolate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose and the like and mixtures thereof.

Pharmaceutically acceptable binders of the invention may be selected from the list comprising starches, natural sugars, corn sweeteners, natural and synthetic gums, cellulose derivatives, gelatin, polyvinylpyrrolidone, polyethylene glycol, waxes, sodium alginate, alcohols, water and the like and mixtures thereof.

Pharmaceutically acceptable lubricants of the present invention may be selected from the list comprising metallic stearates, metallic lauryl sulfates, fatty acids, fatty acid esters, fatty alcohols, paraffins, hydrogenated vegetable oils, polyethylene glycols, boric acid, polyvinylpyrrolidone, sodium benzoate, sodium acetate, sodium chloride, talk and the like and mixtures thereof.

Pharmaceutically acceptable glidants of the present invention may be selected from the list comprising silicon dioxide, magnesium trisilicate, starch, talc, silicon hydrogel and the like and mixtures thereof.

Pharmaceutically acceptable disintegrating agents of the present invention may be selected from the list comprising starches, cellulose derivatives, polyvinylpyrrolidone, crospovidone, clays, ion-exchange resins, alginic acid, sodium alginate and the like and mixtures thereof. The preferred antioxidants of the present invention are phenolic antioxidants selected form butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), propyl gallate (PG) or tert-butyl hydroquinone (TBHQ). It is of considerable importance as the addition of a phenolic antioxidant can increase the effectivity of the viral therapy with niclosamide as phenolic antiooxidants, especially BHT has anti-viral properties against the replication of RNA viruses, hence is used as a multipurpose ingredient within the formulation.

According to the present invention, the composition includes a phenolic antioxidant selected form butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), propyl gallate (PG) and tert-butyl hydroquinone (TBHQ).

Sweeteners suitable for inclusion in the present invention may be determined by one skilled in the art including, for example without limitation, both natural and artificial sweeteners such as the representative sweetening agents of intense sweeteners such as sorbitol, sucrose, saccharin such as sodium saccharin, cyclamates such as sodium cyclamates, aspartame, sucralose, thaumatin, acesulfame K, and the like, and sugars such as monosaccharides, disaccharides and polysaccharides. Representative sugars useful in the present invention include, without limitation, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch or com syrup, and sugar alcohols such as sorbitol, xylitol, mannitol, glycerin, etc. and combination thereof. Presently preferred as a sugar sweetener is sucralose. Sugar sweeteners may be replaced or augmented by water-soluble artificial sweeteners, such as the suitable artificial sweeteners previously listed and mixtures thereof. The amount of artificial sweetener used in the composition may vary to provide an appropriate amount of sweetness as determinable by one skilled in the art. Mixtures of sweetening and/or flavoring agents are preferably used.

Examples of preservatives suitable for use in the present invention include, for example without limitation, one or more alkyl hydroxybenzoates, such as methyl hydroxybenzoates, ethyl hydroxybenzoates, propyl hydroxybenzoates, butyl hydroxybenzoates and the like. Additional preservatives useful in the present invention include, but are not limited to, sodium benzoate, potassium sorbate, salts of edetate (also known as salts of ethylenediaminetetraacetic acid, or EDTA, such as disodium edetate) and antimicrobial agents including parabens (p- hydroxybenzoic acids esters) such as methyl paraben, ethyl paraben, propylparaben, butylparaben and the like, and combinations thereof. Parabens are preferred, with methyl paraben most preferred for use as preservative ingredients to add to the present pharmaceutical composition, although other pharmaceutically acceptable preservatives may be substituted therefore. Preservative(s) as used in the composition are in an acceptable range.

The composition may also contain a viscosity enhancing agent(s) which include but are not limited to gums; sorbitol; glycerol; polyvinyl alcohol; polyvinyl pyrrolidone; polyethylene oxide; cellulose derivatives, such as hydroxypropylmethylcellulose or a salt thereof, alkyl ether of cellulose, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose and mixtures thereof. Preferably the viscosity-enhancing agent is hydroxypropylmethylcellulose e.g. (HPMC K4M, HPMC K100 LVP; HPMC K15 MP; HPMC E4 MP; HPMC E10 MP CR).

The pharmaceutical compositions of the present invention are to be used for the therapeutic or prophylaxis treatment of viral disease and cancer.

Accordingly, the composition of the present invention is used for the therapeutic or prophylaxis treatment of prostate cancer, breast cancer, lung cancer, and colorectal cancer colon cancer, throat cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, uterine cancer, brain cancer, liver cancer, skin cancer, testicular cancer, stomach cancer, adrenal gland cancer, cancer of the ovaries, thyroid cancer, bronchial cancer, trachea cancer, eye cancer, bone cancer, cervical cancer, oral cavity cancer, soft tissue cancer, pituitary gland cancer, myeloma, rectal cancer, esophageal cancer, leukemia, lymphoma, cancerous fibroid tumors, non-cancerous fibroid tumors, or liver cancer.

In addition, the composition of the present invention may be used for the treatment or prophylaxis of conditions caused by viruses.

The viral disease is caused preferably by RNA viruses. Most viruses are classified into broad categories based on the types of nucleic acids formed during replication and the pathway by which mRNA is produced. In general, viruses have either RNA or DNA as their genetic material, wherein the nucleic acid can be single- or double-stranded.

Important virus families of the DNA type include adenoviridae, herpesviridae, poxviridae, papovaviridae, densovirinae, and parvovirinae. Virus families typically classified of the RNA type include birnaviridae, reoviridae, astoviridae, arterivirus, caliciviridae, coronaviridae, flaviviridae, picomaviridae, togaviridae, polioviruses, bornaviridae, filoviridae, paramyxovirinae, pneumovirinae, rhabdoviridae, bunyaviridae, and orthomyxoviridae. Conditions or diseases that can be treated with the composition of the present invention include but are not limited to the Ebola vims disease, SARS, MERS, COVID-19 virus disease, Rabies, influenza A vims disease, influenza B vims disease, hepatitis C, West Nile vims disease and ZIKA vims disease; preferably COVID-19 vims disease.

As described above, niclosamide has a potential therapeutic effect of these diseases however because of its low solubility, this potential is not shown. Low solubility causes low bioavailability leading to low poor pharmacokinetic profile, which results in limited efficacy as a therapeutic for human use in the treatment of cancer or viral disease. According to the present invention, a single unit dose composition comprises niclosamide in an amount of from 200 to 2000 mg, preferably 300 to 1500 mg and more preferably 300 to 1000 mg, most preferably 350 to 750 mg per unit dose.

According to the present invention, the composition comprises at least one alkalizing agent in an amount of from 100 to 2000 mg, preferably 200 to 1800 mg and more preferably 300 to 1000 mg per unit dose.

Although, there were other possible candidates for dmg repositioning as an antiviral. Apart from the in-vitro success of niclosamide another reason why, niclosamide was chosen by the inventor is that niclosamide has a very low amount of interactions with other drugs and hence can be co-administered with most other anti-cancer and anti- viral therapies. Due to the complexity of these diseases it is important that at least one other drug be given at the same time, before or after the treatment done with the composition of the present invention.

In one preferred embodiment of the present invention, to increase the effectiveness of an anti viral treatment, niclosamide composition of the present invention is administered with at least one other antiviral compound, at least one anticancer compound and/or at least one antibiotic compound.

Accordingly, the composition of the present invention may be administered before/after/during treatment with favipiravir, oseltamivir, hydroxychloroquine sulphate, chloroquine phosphate, lopinavir/ritonavir, remdesivir, interferon alpha and interferon beta, azithromycin, budesonide.

For the avoidance of doubt, the term “before/after/during” means that the niclosamide composition of the present invention is administered during another interventional treatment or within 7 days before or after another interventional treatment. In the most preferred embodiment, the niclosomide composition of the present invention is administered within 24 hours of another interventional treatment. Specifically, the composition of the present invention is administered with at least one other antiviral compound, at least one anticancer compound and/or at least one antibiotic compound within 24 hours.

The oral unit dosage forms prepared with the composition of the present invention can be administered 2 to 3 times daily. The total daily dose of niclosamide administered is preferably less than 2000 mg due to the superior solubility and significant bioavailability that can be attained. Thus, the treatment regimen for niclosamide will be twice or thrice a day with a total daily dose between 1000 mg and 2000 mg for the treatment of viral diseases and cancer. Specifically, the pharmaceutical composition is administered two or three times a day up to a maximum daily dose of 1800 mg, the amount of niclosamide or a pharmaceutically acceptable derivative is between 300 and 750 mg per single unit dose.

In another preferred embodiment, the single unit dose of niclosamide administered with the composition of present invention is between 300 and 600 mg.

In the most preferred embodiment, the single unit dose of niclosamide administered with the composition of present invention is 350 to 500 mg, wherein the unit dose is administered three times a day.

A prophylactic dose of 500 mg daily can also be administered to high risk patients during viral disease outbreaks.

The present invention provides the pharmaceutical composition for use in the therapeutic or prophylactic treatment of cancer, wherein the composition is administered a period of 20 days to 3 months. The present invention also provides the pharmaceutical composition for use in the therapeutic or prophylactic treatment of viral disease, wherein the composition is administered a period of 5 to 15 days.

Another preferred embodiment of the present invention entails the use of the composition of the present invention containing 1000 to 1500 mg of niclosamide, separated into two or three doses for a period of 5 to 15 days for the therapeutic or prophylactic treatment of viral disease. The most preferred embodiment of the present invention entails the use of the composition of the present invention containing 350 to 500mg of niclosamide two times a day for a period of 21 days to 90 days (3 months) for the therapeutic or prophylactic treatment of cancer.

In another embodiment, the present invention provides a process to obtain the oral composition comprising, the step of mixing niclosamide with at least one emulsifier and at least one alkalizing agent for at least 20 minutes. The mixing is preferably performed in a liquid mixing tank at 100 RPM or higher. The process further comprises the addition of at least one dextrin compound and other pharmaceutically acceptable excipients.

The mixing can also be performed through the use of a high sheer mixer, tumbler, fluid bed dryer or spray dryer depending on the process and emulsifier employed.

The process according to the present invention can further comprise the steps of mixing niclosamide, at least one alkalizing agent and at least one dextrin compound with an emulsifier, an antioxidant, a flavoring agent and a viscosity enhancer, as well as other pharmaceutically acceptable excipients known by one with ordinary skill in the art.

The process according to the present invention preferably comprises the steps of:

1. Mixing niclosamide and an emulsifier under room temperature with high sheer mixer at 500 rpm for 60 minutes,

2. Adding the dextrin compound and continue mixing for 10 minutes at 500 rpm,

3. Adding the alkalizing agent and BHT,

4. Optionally adding a flavoring agent, and

5. Adding QS water and mixing at 100 RPM for 15 minutes.

If the formulation employs a liquid emulsifier like tween 80 and needs to be converted into powder form or granules to be reconstituted with water:

1. Mixing niclosamide and emulsifier under room temperature with high sheer mixer at 500 rpm for 60 minutes,

2. Adding the dextrin compound and continue mixing for 10 minutes at 500 rpm,

3. Adding the alkalizing agent and BHT continue mixing for 10 more minutes,

4. Adding a silica derivative and continue mixing at 50 to 150 RPM until the composition is in powder form, and

5. optionally adding a flavoring agent. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

EXAMPLES

Example 1

120 ML Suspension formulation and manufacturing process

Manufacturing Process

1. 105 kg of niclosamide anhydrous and 840 kg of polysorbate 80 is weighed and mixed by using a liquid tank with mixer at 50 rpm for 10 minutes, followed by 500 RPM for 60 minutes; 2. 63 kg of maltodextrin and 63 kg of sodium bicarbonate is weighed and added to the mixture in the mixer and mixed for another 10 minutes at 500 RPM;

3. 1.05 kg of BHT and 2,1 kg of mint flavor is weighed and added to the mixture in the high sheer mixer and mixed for another 10 minutes at 500 RPM;

4. 125,85 liters of water is added to the mixture and mixed for 20 minutes at 50 RPM; and 5. the resulting suspension solution is filled into bottles with a 150ml volume at a filling volume of 120ml.

Each bottle containing 120 ml of niclosamide suspension contains 21 single unit doses of 500 mg each, equal to about 5,7 ml per dosing. Which will preferably be administered 3 times a day within a 24-hour period or twice a day, with a dose of about 8,56 ml for a single unit dose of 750 mg niclosamide.

The dosing with the suspension will preferably be done with, and administered with an oral injector for ease of use.

Method: UV, Spectrophotometer Shimadzu 1800 Dissolution Solvent: Methanol Wavelength: 332 nm

Preparation of Niclosamide Standard Solution:

Niclosamide reference standard was dissolved in methanol at 0.05 mg/ml concentration.

500 mg dissolved Niclosamide standard was weighed in a 100 ml volumetric flask.

50 ml Methanol was added onto the niclosamide standard and kept in an ultrasonic bath for 20 minutes. Volume was added up to 100 ml and filtrated by using 0.45 pm PTFE filter. 1 ml of the standard solution was completed to 100 ml by methanol. Absorbance value was measured at 332 nm (C Mciosamid: 0.05 mg/mL).

Preparation of Test Solutions:

500 mg Niclosamide and excipients of 11 test compositions were dissolved in 30 ml phosphate buffer at pH:6,8 and kept in an ultrasonic bath for 1 hour and centrifuged 10 minutes at 1000 rpm. Supernatants were collected and 0.34 ml of supernatants were dissolved in methanol and added up to 100 ml. Absorbance value was measured at 332 nm (C _Mciosamid: 0.05 mg/mL).

Table 1 - Test compositions

* Concentration of niclosamide that is solubilized at pH 6.8 as detected by the Spectrophotometric method. Table 2 - Solubility Results

Animal Study

A total of 48 Male Sprague-Dawley rats of 330-380g were divided into 6 groups and fasted for 12 hours prior to oral dosing. The test compositions (Table 1) were administered 5-mg/kg of niclosamide per test dose by oral gavage. The dosing solutions were used according to the Test composition examples. Blood samples of 150 pL were collected via the tail veins at 15 and 30 min and at 1, 2, 4, 6, 8, 12 and 24 hours after compound administration into EDTA containing tubes and kept on ice.

The samples were analyzed with an HPLC system with a reverse-phase column, interfaced to a tandem mass spectrometer. Mobile phase consisted of 10 mM ammonium acetate containing 0.1% of formic acid (Solvent A) and acetonitrile (Solvent B). The following stepwise gradient system was used: 70% A to 2% A (0-0.5 min), 2% A (0.5-4.0 min), 2% A to 70% A (4.0-4.5 min), 70% A (4.5-7.0 min). Total running time was 7 min. The retention time was 1.9 min.

Study results

Evaluation of the results

The highly synergistic effect of the composition of the present invention is demonstrated by the fact that the singular composition of an emulsifier; Polysorbate 80 (test composition 1) with niclosamide has provided a niclosamide concentration of about 73mg/ml in SIF at pH 6.8. and the composition of niclosamide with tween 80 and beta cyclodextrin (test composition 2) has provided about 75mg/ml solubility and the composition of niclosamide with tween 80 and maltodextrin has provided about 98 mg/ml, whereas the composition of the present invention with maltodextrin, Tween 80 and an alkalizing agent has provided about 124 mg/ml of solubility in intestinal pH.

As it can be seen in the solubility results, contrary to prior art; the addition of organic acids (ie: citric acid and stearic acid) with pH decreasing effects has a negative effect on the solubility of niclosamide with all of the variations of the excipients and the addition of an alkalizing agent; sodium bicarbonate significantly increases the solubility of niclosamide.

Similar results paralleling the results of the solubility study were obtained with the animal study, also demonstrating the positive effects of the compositions on blood concentrations.

Thus, the niclosamide composition manufactured with a dextrin compound, an alkalizing agent and an emulsifier, preferably with a HLB value higher than 10, creates a substantial synergistic effect, especially when mixed at specific ratios, whilst employing less of a dextrin compound compared to the prior art. This effect results to a better Niclosamide solubility and bioavailability.

Claims

1. An oral pharmaceutical composition comprising niclosamide or a pharmaceutically acceptable derivatives thereof, at least one emulsifier and at least one dextrin compound.

2. A pharmaceutical composition according to claim 1, further comprising at least one alkalizing agent.

3. A pharmaceutical composition according to claims 1 or 2, wherein the weight ratio of the dextrin compound to the emulsifier is between 1:1 to 1:20.

4. A pharmaceutical composition according to any one of preceding claims, wherein the weight ratio of the dextrin compound to the emulsifier is between 1:5 to 1:15.

5. A pharmaceutical composition according to any one of preceding claims, wherein the weight ratio of niclosamide to the dextrin compound is between 10:1 to 1:2.

6. A pharmaceutical composition according to any one of preceding claims, wherein the weight ratio of niclosamide to the dextrin compound is between 5:1 to 1:1.

7. A pharmaceutical composition according to any one of preceding claims, wherein the weight ratio of niclosamide to the alkalizing agent is between 10:1 to 1:2.

8. A pharmaceutical composition according to claim 7, wherein the weight ratio of niclosamide to the alkalizing agent is between 5:1 to 1:3.

9. A pharmaceutical composition according to claim 8, wherein the weight ratio of niclosamide to the alkalizing agent is between 2:1 to 1:2.

10. A pharmaceutical composition according to any one of preceding claims, wherein the emulsifier has an HLB value between 10 and 25.

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein the emulsifier: is selected from the group consisting of polyoxethylene derivatives, sorbitan esters, polyethylene glycol derivatives and a combination thereof.

12. A pharmaceutical composition according to any one of claims 1 to 11, wherein the emulsifier: is selected from the group consisting of tearoyl polyoxyl-32 glycerides, lauroyl polyoxyl-32 glycerides or polyoxy-ethylene sucrose diester dimyristate, Polyoxy- ethylene sucrose diester dinnyristate, polyoxy-ethylene sucrose diester dipalmitate, polyoxy-ethylene sucrose diester dioleate, polysorbate 80, polysorbate 60, polysorbate 20, PEG-8 laurate, PEG 400 monoluarate, PEG 10 isooctylphenyl ether, PEG 40 stearate, PEG 50 stearate, PEG 40 isooctylphenyl ether, sodium stearoyl-2-lactylate, sodium stearoyl lactylate and a combination thereof.

13. A pharmaceutical composition according to any one of the preceding claims, wherein the emulsifier is a polyoxylglyceride or a polysorbate.

14. A pharmaceutical composition according to claim 13, wherein the emulsifier is selected from the group consisting of polysorbate 80, polysorbate 60, polysorbate 20, and a combination thereof.

15. A pharmaceutical composition according to claim 13, wherein the polyoxylglyceride is selected from the group consisting of stearoyl polyoxyl-32 glyceride, lauroyl polyoxyl-32 glyceride and a combination thereof.

16. A pharmaceutical composition according to any one of the preceding claims, wherein the dextrin compound is selected from the group consisting of a-cyclodextrin, g-cyclodextrin, b-cyclodextrin, 2-hydroxypropyl-P-cyclodextrin, sulfobutylether b -cyclodextrin sodium salt, randomly methylated b-cyclodextrin, branched b-cyclodextrin, maltodextrin and derivatives thereof.

17. A pharmaceutical composition according to claim 16, wherein the cyclodextrin compound is selected from the group consisting of b-cyclodextrin, 2-hydroxypropyl^- cyclodextrin, sulfobutylether b-cyclodextrin sodium salt, randomly methylated b-cyclodextrin, branched b-cyclodextrin, maltodextrin and derivatives thereof.

18. A pharmaceutical composition according to any one of the preceding claims, wherein the alkalizing agent is selected from the group consisting of: sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, magnesium carbonate, ammonium carbonate, ammonium bicarbonate, potassium carbonate, potassium bicarbonate, sodium glycine carbonate, disodium glycine carbonate, arginine carbonate, arginine bicarbonate, lysine carbonate, potassium hydroxide, magnesium hydroxide, potassium chloride, sodium hydroxide, potassium hydroxide, ammonium hydroxide, methanolamine, monoethanol amine, propanolamine, arginine, lysine, methylene diamine, ethylene diamine, and propylene diamine.

19. A pharmaceutical composition according to any of the preceding claims, further comprising an antioxidant.

20. A pharmaceutical composition according to claim 19, wherein the antioxidant is selected from phenolic antioxidants which are butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), propyl gallate (PG) or tert-butyl hydroquinone (TBHQ).

21. A pharmaceutical composition according to any of the preceding claims, further comprising a silica derivative, selected from the group consisting of colloidal silicon dioxide, calcium silicate and magnesium aluminometasilicate.

22. A pharmaceutical composition according to claim 21, wherein the particles of the silica derivative have a mean grain diameter between 10 to 250 microns, a BET surface area between 150 m2/g and 400 m2/g, and has a tamped density between 50 to 500g/L.

23. A pharmaceutical composition according to any one of the preceding claims for use in the therapeutic or prophylactic treatment of cancer or viral disease.

24. A pharmaceutical composition for use according to claim 23, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer, colorectal cancer, colon cancer, throat cancer, kidney cancer, pancreatic cancer, bladder cancer, uterine cancer, brain cancer, skin cancer, testicular cancer, stomach cancer, adrenal gland cancer, cancer of the ovaries, thyroid cancer, bronchial cancer, trachea cancer, eye cancer, bone cancer, cervical cancer, oral cavity cancer, soft tissue cancer, pituitary gland cancer, myeloma, rectal cancer, esophageal cancer, leukemia, lymphoma, cancerous fibroid tumors, non-cancerous fibroid tumors, or liver cancer.

25. A pharmaceutical composition for use according to claim 23, wherein the viral infection is selected from the group consisting of the Ebola vims disease, SARS, MERS, COVID-19 virus disease, Rabies, influenza A virus disease, influenza B vims disease, hepatitis C, West Nile vims disease and ZIKA vims disease.

26. A pharmaceutical composition for use according to claim 25, wherein the viral infection is COVID-19 vims disease.

27. A pharmaceutical composition for use according to any one of claims 23 to 26, wherein the amount of niclosamide is between 200 and 1800 mg per single unit dose.

28. A pharmaceutical composition for use according to claim 27, wherein the amount of niclosamide is between 300 to 1500 mg.

29. A pharmaceutical composition for use according to claim 27, wherein the amount of niclosamide is between 350 to 750 mg.

30. A pharmaceutical composition for use according to any one of claims 23 to 29, wherein the pharmaceutical composition is administered two or three times a day up to a maximum daily dose of 1800 mg.

31. A pharmaceutical composition for use according to any one of claims 23 to 30, wherein the composition is administered with at least one other antiviral compound or at least one anticancer compound and/or at least one antibiotic compound within 24 hours.

32. A pharmaceutical composition for use according to claim 23 in the therapeutic or prophylactic treatment of cancer, wherein the composition is administered a period of 21 days to 3 months.

33. A pharmaceutical composition for use according to claim 23 in the therapeutic or prophylactic treatment of viral disease, wherein the composition is administered a period of 5 to 15 days.