WO2021201796A1

WO2021201796A1 - Targeted release of niclosamide compositions with high solubility and bioavailability

Info

Publication number: WO2021201796A1
Application number: PCT/TR2020/050801
Authority: WO
Inventors: Mehmet Nevzat PISAK
Original assignee: Imuneks Farma Ilac San. Ve Tic.A.S
Priority date: 2020-04-01
Filing date: 2020-09-03
Publication date: 2021-10-07

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 enteric oral composition comprising niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates and esters targeting the intestinal release of niclosamide.

Description

TARGETED RELEASE OF NICLOSAMIDE COMPOSITIONS WITH HIGH

SOLUBILITY AND BIOAVAILABILITY

DESCRIPTION

TECHNICAL FIELD

The present invention provides an enteric coated oral composition comprising niclosamide or a pharmaceutically acceptable derivatives such as salts, hydrates and esters and also provides a manufacturing process of said composition and also solves the solubility and bioavailability problems in the prior art.

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) vims 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 coronavims (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 coronavims infections are typically mild and rarely associated with severe diseases. However, the epidemics of Middle East respiratory syndrome coronavims (MERS-CoV) and severe acute respiratory syndrome coronavims (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.

The usual oral dose of niclosamide is 2000 mg as a single dose daily for 7 days, followed by 1000 mg for 6 days; including pediatric patients 6 years and older. But the use of drug is limited by side effects. Niclosamide is absorbed from the intestines but evidently go through the stomach, conventionally tablets are given on an empty stomach in the morning in order to enhance its dissolution and absorption. But this dosage regime generally causes gastrointestinal side effects.

In a study evaluating antiviral activity of niclosamide, activity against SARS-CoV strains of the molecule was demonstrated in vitro (Xu et al., ACS Infect. Dis 2020, 6, 909-915). In another antiviral activity study, the antiviral potential of niclosamide was shown against various virus strains including influenza, in vitro (Antimicrobial Agents and Chemotherapy 48(7):2693-6). In regard of these evidences including in vitro results (IC50 = 3.12 mM) against SARS CoV strains presented and plasma concentration estimation of 400 mg oral dose (3.6 pMjindicating that 400 mg oral dose of niclosamide is an adequate dose to create an effective concentration for SARS CoV.

However, the use of niclosamide has a major disadvantage; low solubility, low bioavailability and poor pharmacokinetic profile, which results in limited efficacy as a therapeutic for human use in the viral disease indication. In press release of Institut Pasteur and Daewoong Holding declare that they are developing niclosamide for the COVID-19 treatment; despite its excellent antiviral effect on COVID-19, niclosamide had a problem of maintaining blood drug concentrations in the human body when taken orally, making it difficult to be applied as an actual treatment for COVID-19.

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 2000 mg a day, or even 1500 mg 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 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. Thus, it has been shown by this study that the solubility of niclosamide increases with the use of an acidic substance. 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.

It is clear from the prior art that the 2 main issues to be solved regarding niclosamide’ s use as an efficient and safe therapeutic as an antiviral agent and anti-cancer agent are; the problem of solubility and the problem of gastrointestinal toxicity/side effects. Thus, there is still a need in the art for a pharmaceutical composition which is effective in viral diseases, and also which is safe to use without side effects; in addition 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 and esters, solving the solubility and bioavailability problems of niclosamide in the prior art with a simple manufacturing process.

The present invention provides an enteric coated pharmaceutical composition comprising niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates and esters, at least one emulsifier targeted to be released in the intestines.

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

In another aspect, the present invention provides a pharmaceutical composition comprising a niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates and esters with at least one emulsifier having a HLB value between 10 and 25 and at least 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 and esters with at least one emulsifier having a HLB value between 10 and 25, 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 4000, 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 and sodium lauryl sulphate. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an enteric coated oral pharmaceutical composition comprising a core having niclosamide or a pharmaceutically acceptable derivatives thereof and at least one emulsifier, and at least one enteric coating. Thus, the composition is targeted to be released in the intestines.

Niclosamide composition of the present invention will not be released at a pH of less than 3. The so-coated enteric release formulations have good resistance to deterioration at pH less than 3 but have good drug release properties at greater than 3, targeting the intestinal release of niclosamide.

As mentioned, the prior art does not disclose any enteric coated, niclosamide preparations due to the low solubililty and bioavailability of niclosamide, because even if the niclosamide powder as an active ingredient is formulated into a form to be released in the intestines (i.e.; formulated as an enteric coated tablet, filled into an delayed release capsule shell or enteric coated pellets to be released in the intestines) the solubility of niclosamide remains nearly as low as the unformulated powder. In addition, the prior art teached away the use of enteric coated formulations for niclosamide as they disclose the increase of niclosamide solubility in the acidic environment. However, while solving the solubility and bioavailability problem of niclosamide, the present composition decreases gastrointestinal side effects of niclosamide and also protects the niclosamide matrix from degradation which would help maintain the solubility and permeability of niclosamide at the targeted sight of absorption, which is the intestines.

Although substantially higher levels of solubility compared to prior art can be achieved with the composition of the present invention comprising an emulsifier such as a sorbitan ester (polysorbate 80) and preferably a dextrin compound such as beta-cyclodextrin or maltodextrin; it has also been surprisingly discovered that formulating niclosamide into an enteric coated tablet form to be released in the intestines, would protect patients from gastrointestinal side effects of niclosamide more effectively, while also protecting the matrix formulation encapsulating niclosamide, emulsifier and dextrin compound from the acidic (low pH) environment and acid hydrolysis to niclosamide. The non-formulated niclosamide anhydrous active pharmaceutical ingredient was surprisingly observed to be more soluble at the simulated intestinal fluid pH of 6.8, as it can be seen in the dissolution study. Thus, the present invention is focused on the targeted release of niclosamide in the intestines, preferably in the small intestines, to obtain a higher solubility at the pH level of 6.8. The existing superior properties (solubility) of the composition comprising an emulsifier and preferably a dextrin compound and its effects are explained in detail within the patent applications TR2020/05165, TR2020/06655 and TR 2020/10775.

In a preferred embodiment; the enteric coating of the targeted release niclosamide compositions is a polymer-based coating and comprises a polymer compound selected from the group consisting of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, ethyl cellulose, cellulose acetate benzenetricarboxylic acid ester, carboxymethylethyl cellulose, methylmethacrylate- methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylatechloride copolymer, methylmethacrylate- ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, the diketopiperazine polymer, Lac, zein, at least a triethyl citrate and polyvinyl acetate phthalate; preferably methacrylic acid-ethyl acrylate copolymer.

According to the present invention, the enteric coating may further comprise a plasticizer which is selected from the group consisting of diethyl phthalate, dimethyl phthalate, dibutyl phthalate, Polyethylene Glycol (PEG), hexadecanol, glycerol triacetate, Lac, octadecanol.

In another preferred embodiment; the enteric coated pharmaceutical composition may further comprise an intermediate layer between the core and enteric coating. This intermediate layer prevents the interaction of niclosamide with the enteric (enteric) shell, which can lead to discoloration of niclosamide and its loss over time.

The gastric passage time of the enteric coated niclosamide may vary between among the patients, thus in order to have less inter subject variability, a primary coating material is applied to protect the integrity of the core, before the enteric coating is applied. Furthermore, it has been observed that some enteric coating material may create impurities within the core formulation of niclosamide, thus the primary coating serves a dual purpose.

The above described targeted release niclosamide compositions may be in the form of niclosamide enteric coated micropill, niclosamide enteric coatel tablets, niclosamide enteric hard capsule, niclosamide enteric coated pellets, niclosamide enteric-coated micropellets. Preferably, niclosamide is formulated into an enteric coated tablet, filled into a delayed release capsule shell as powder or enteric coated pellets to be released in the intestines.

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

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 (Dierucat), 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), Poly glyceryl- 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 Laurie 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.

According to the present invention, the composition comprises niclosamide in an amount of 5% to 30%, preferably 5% to 25% and more preferably 10% 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.

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 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 and 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 (Bmnauer, 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 semi liquid niclosamide composition is loaded on to the silica derivative with a silica derivative to niclosamide ratio of. 1:7 to 1:1 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 solid tablet or capsule form. Or alternatively another preferred emulsifier of the present invention Acconon C50 can be employed with, or instead of tween 80, in which case the silica derivative will be used to a lesser degree, 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 10 and 60%, preferably 10 to 50% more preferably 10 to 40% and most preferably 20 to 40% 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 and 20%, preferably 1 to 15% and more preferably 2 to 13% 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. 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 animal study in the inventor’s previous patent application numbered TR2020/05165.

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

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

In a preferred embodiment, the weight ratio of niclosamide to the emulsifier(s) is between 1:1 and 1:12, preferably 1:3 to 1:10. In order to decrease gastro intestinal side effects with critically ill patients, the preferred oral dosage forms of the present invention have an enteric release profile, wherein release of niclosamide is delayed until the tablet core/capsule reaches the intestine. This release characteristic is chosen to protect the stomach from niclosamide and to protect niclosamide from hydrolysis in the stomach.

In another embodiment of the present invention, the enteric coated oral pharmaceutical composition does not include any alkalizing agent. Because said pharmaceutical composition aims to disintegrate in the intestines, the use of alkalizing agents is not necessary for the present formulation.

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

Pharmaceutically acceptable lubricants of the present invention may be selected from 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 or mixtures thereof.

Pharmaceutically acceptable glidants of the present invention may be selected from silicon dioxide, magnesium trisilicate, starch, talc, silicon hydrogel and the like or mixtures thereof. Pharmaceutically acceptable disintegrating agents of the present invention may be selected from starches, cellulose derivatives, polyvinylpyrrolidone, crospovidone, clays, ion-exchange resins, alginic acid, sodium alginate and the like or 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 corn 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 microcrystalline cellulose, 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 vims 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, picornaviridae, 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 vims 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 targeted release unit dose composition comprises niclosamide in an amount of from 100 to 500 mg, preferably 100 to 400 mg and more preferably 100 to 300 mg, most preferably 150 to 250 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, and/or at least one antibiotic compound.

In another preferred embodiment of the present invention, to increase the effectiveness of the cancer treatment, niclosamide composition of the present invention is administered with at least one other anticancer 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 niclosamide 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 1500 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 300 mg and 1200 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 1200 mg, the amount of niclosamide or a pharmaceutically acceptable derivative is between 100 and 350 mg per single unit dose. In another preferred embodiment, the single unit dose of niclosamide administered with the composition of present invention is between 100 and 300 mg.

In the most preferred embodiment, the single unit dose of niclosamide administered with the composition of present invention is 100 to 250 mg, wherein the unit dose is administered three times a day.

A prophylactic dose of 400 to 600 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 for 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 300 to 1200 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.

In another preferred embodiment of the present invention entails the use of the composition of the present invention containing 150 to 250mg 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.

The most preferred embodiment of the present invention entails the use of the composition of the present invention containing 150 to 250mg of niclosamide three times a day for a period of 5 to 15 days for the therapeutic or prophylactic treatment of viral disease. 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 for at least 20 minutes.

The mixing is preferably performed in a high sheer mixer 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, and at least one dextrin compound with an emulsifier, an antioxidant, a a disintegrating agent, 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 dextrin compound under room temperature with high sheer mixer at 300 rpm for 20 minutes,

2. Adding the emulsifier(s) and continue mixing for 40 minutes at 500 rpm,

3. Adding the silica derivative and continue mixing for 10 more minutes,

4. Adding the viscosity enhancing agent(s) and disintegrating agent (eg; HPMC and MCC and crospovidone.) and continue mixing at 50 to 150 RPM

5. Sieving the mixture

6. Compress the tablets from the sieved mixture

7. Primary coating to protect the tablet and matrix

8. Secondary enteric coating for the targeted release of the formulation in the intestines sieving the mixture.

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

Contents of Coatings in all examples:

Manufacturing Method:

1. Mix niclosamide and maltodextrin

2. Add Tween 80 and PEG 4000 mix 30 minutes. 3. Add Aeroperl 300 and mix 10 minutes

3. Add HPMC and MCC and crospovidone

4. Sieve

5. Add magnessium stearate

6. Compression 7. Primary coating

8. Secondary Coating

Example 2

Manufacturing Method:

1. Mix niclosamide and maltodextrin

2. Add Tween 80 and sodium lauryl sulphate mix 30 minutes. 3. Add Aeroperl 300 mix 10 minutes

3. Add HPMC and MCC and crospovidone.

4. Sieve

5. Add magnessium stearate

6. Compression 7. Primary coating

8. Secondary Coating

Example 3

Manufacturing Method:

1. Mix niclosamide and maltodextrin

2. Add Tween 80 and mix 30 minutes.

3. Add Aeroperl 300 and mix 10 minutes 3. Add HPMC and MCC and crospovidone

4. Sieve

5. Add magnessium stearate

6. Compression

7. Primary coating 8. Secondary Coating

Example 4

Manufacturing Method: 1. Mix niclosamide and maltodextrin

2. Add Tween 80 and Acconon C-50 mix 30 minutes. 3. Add Aeroperl 300 mix 10 minutes

3. Add HPMC and MCC and crospovidone.

4. Sieve

5. Add magnessium stearate 6. Compression

7. Primary coating

8. Secondary Coating

Example 5

Manufacturing Method:

1. Mix niclosamide and maltodextrin

2. Add Tween 80 and mix 30 minutes.

3. Add Aeroperl 300 mix 10 minutes 3. Add HPMC and MCC, crospovidone and BHT.

4. Sieve 5. Add magnessium stearate

6. Compression

7. Primary coating

8. Secondary Coating

Example 6

Manufacturing Method:

1. Mix niclosamide and maltodextrin 2. Add Tween 80, Acconon C-50 and mix 30 minutes.

3. Add Aeroperl 300 mix 10 minutes

3. Add HPMC and MCC

4. Sieve

5. Add magnessium stearate 6. Fill the final mixture into capsules

Niclosamide Dissolution Test (in simulated intestinal fluid pH:6,8 phosphate buffers)

The dissolution study was performed using a USP Type II dissolution apparatus, the details are given below. HPLC ANALYSIS

Chromatographic System : Equipment: High Pressure Liquid chromatography (HPLC)

Column : InertSustain C18 ; 250x4.6 mm, 5pm Flow Rate : 1.5 mL/min/ (1.5 mL/min.)

Wavelenght : 230 nm Injection Volume : 3 pL

Column Temperature : 25 °C Sample Temperature : 25 °C Injection Time : 7 minutes Retention Time for Niclosamide ~ 5.3 minutes Mobile Phase : Buffer (MPA): Organic (MPB) (30:70 v/v) Dissolution Medium : pH 6.8 Phosphate Buffer Dissolution Medium Volume : 900 mL Apparatus : Pedal Speed : 100 rpm Target Time : 60 minutes

RESULTS

Table 1 - Certificate of Analysis for Example 4

Dissolution Test Results with the formulation of Example 4

Table 2 - Dissolution Results at pH:6.8 Phosphate Buffer

Table 3 - Dissolution Results at 0.1 N HC1

Table 4 - Dissolution Results at pH:4.5 Phosphate Buffer

Since the pH 1.2 simulates the gastric fluid, the results demonstrate that very negligible amounts of niclosamide is released in the stomach, taking into consideration a median gastric passage time of about an hour. The dissolution study shows that only 0,03% of niclosamide is released with only one of the samples, within 60 minutes. Thus, the enteric coated niclosamide composition of the present invention is minimally released in the acidic environment of the stomach and released significantly more in the medium simulating the 6.8 pH intestinal fluid, thus demonstrating that the niclosamide composition of the present invention targeted to be released in the intestines has higher solubility and consequentially higher bioavailability and will cause less irritation to the stomach due to significantly less niclosamide being released in the stomach. Worspe, J., Fynne, L., Gregersen, T. et al. Gastric transit and small intestinal transit time and motility assessed by a magnet tracking system. (BMC Gastroenterol 11, 145 (2011). https://doi.org/10.1186/1471-230X- 11-145)

Claims

1. An oral pharmaceutical composition comprising a core having niclosamide or pharmaceutically acceptable derivatives thereof and at least one emulsifier, and at least one enteric coating.

2. A pharmaceutical composition according to claim 1, wherein the core further comprises at least one dextrin compound.

3. A pharmaceutical composition according to claim 1 or 2, wherein the amount of niclosamide is between 100 and 500 mg in the core.

4. A pharmaceutical composition according to claim 3, wherein the amount of niclosamide is between 100 and 400 mg in the core.

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

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

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

8. A pharmaceutical composition according to any one of preceding claims, wherein the weight ratio of niclosamide to the dextrin compound is between 6:1 and 3:1.

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

10. A pharmaceutical composition according to any one of claims 1 to 9, wherein the emulsifier is selected from the group consisting of polyoxethylene derivatives, sorbitan esters, polyethylene glycol derivatives and a combination thereof.

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein the emulsifier is selected from the group consisting of 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, polysorbate 80, polysorbate 60, polysorbate 20, PEG-8 laurate, PEG 400 monoluarate, PEG 10 isooctylphenyl ether, PEG 40 stearate, PEG 4000, PEG 50 stearate, PEG 40 isooctylphenyl ether, sodium stearoyl-2-lactylate, sodium stearoyl lactylate and a combination thereof.

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

13. A pharmaceutical composition according to claim 9, wherein the emulsifier is selected from the group consisting of polysorbate 80, polysorbate 60, polysorbate 20, stearoyl polyoxyl-32 glycerides, lauroyl polyoxyl-32 glycerides, PEG 4000 and a combination thereof.

14. A pharmaceutical composition according to claim 9, wherein the polyoxylglyceride is selected from the group consisting of stearoyl polyoxyl-32 glyceride, lauroyl polyoxyl-32 glyceride and a combination thereof.

15. 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.

16. A pharmaceutical composition according to claim 15, 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.

17. A pharmaceutical composition according to any one of the preceding claims, wherein the enteric coating comprises a polymer compound selected from the group consisting of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, ethyl cellulose, cellulose acetate benzenetricarboxylic acid ester, carboxymethylethyl cellulose, methylmethacrylate- methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylatechloride copolymer, methylmethacrylate- ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, the diketopiperazine polymer, Lac, zein, at least a triethyl citrate and polyvinyl acetate phthalate.

18. A pharmaceutical composition according to claim 17, wherein the polymer compound is methacrylic acid-ethyl acrylate copolymer.

19. A pharmaceutical composition according to any one of the preceding claims, further comprising at least one intermediate coating between the core and the enteric coating.

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

21. A pharmaceutical composition according to claim 20, 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).

22. 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.

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

24. An oral pharmaceutical composition for use according to any preceding claims, wherein 1% to 6% of niclosamide is released within 30 minutes when subjected to an in vitro dissolution test at 100 rpm in 900 mL of pH 6.8 phosphate buffer and at 37.0°C. ± 0.5°C.

25. An oral pharmaceutical composition for use according to claim 24, wherein 1% to 6% of niclosamide is released within 60 minutes when subjected to an in vitro dissolution test at 100 rpm in 900 mL of pH 6.8 phosphate buffer and at 37.0°C. ± 0.5°C.

26. A pharmaceutical composition according to any one of the preceding claims for use in the therapeutic or prophylactic treatment of cancer or diseases caused by RNA viruses.

27. A pharmaceutical composition for use according to claim 26, 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.

28. A pharmaceutical composition for use according to claim 27, wherein the viral infection is selected from the group consisting of the Ebola virus disease, SARS, MERS, COVID-19 virus disease, Rabies, influenza A virus disease, influenza B virus disease, hepatitis C, West Nile virus disease and ZIKA virus disease.

29. A pharmaceutical composition for use according to claim 28, wherein the viral infection is COVID-19 virus disease.

30. A pharmaceutical composition for use according to any one of claims 26 to 29, wherein the amount of niclosamide is between 100 and 400 mg per single unit dose.

31. A pharmaceutical composition for use according to claim 30, wherein the amount of niclosamide is between 150 and 250 mg.

32. A pharmaceutical composition for use according to claim 31, wherein the amount of niclosamide is 200 mg.

33. A pharmaceutical composition for use according to any one of claims 26 to 32, wherein the pharmaceutical composition is administered two or three times a day up to a maximum daily dose of 1200 mg.

34. A pharmaceutical composition for use according to any one of claims 26 to 33, 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.

35. A pharmaceutical composition for use according to any one of the preceding claims claim in the therapeutic or prophylactic treatment of cancer, wherein the composition is administered for a period of 21 days to 3 months.

36. A pharmaceutical composition for use according to any one of the preceding claims in the therapeutic or prophylactic treatment of viral disease, wherein the composition is administered for a period of 5 to 15 days.