WO2021201796A1 - Libération ciblée de compositions de niclosamide à solubilité et à biodisponibilité élevées - Google Patents

Libération ciblée de compositions de niclosamide à solubilité et à biodisponibilité élevées Download PDF

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WO2021201796A1
WO2021201796A1 PCT/TR2020/050801 TR2020050801W WO2021201796A1 WO 2021201796 A1 WO2021201796 A1 WO 2021201796A1 TR 2020050801 W TR2020050801 W TR 2020050801W WO 2021201796 A1 WO2021201796 A1 WO 2021201796A1
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Prior art keywords
pharmaceutical composition
cancer
niclosamide
peg
composition according
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PCT/TR2020/050801
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English (en)
Inventor
Mehmet Nevzat PISAK
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Imuneks Farma Ilac San. Ve Tic.A.S
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Priority claimed from TR2020/05165A external-priority patent/TR202005165A2/tr
Priority claimed from TR2020/10775A external-priority patent/TR202010775A2/tr
Application filed by Imuneks Farma Ilac San. Ve Tic.A.S filed Critical Imuneks Farma Ilac San. Ve Tic.A.S
Publication of WO2021201796A1 publication Critical patent/WO2021201796A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/609—Amides, e.g. salicylamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • 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].
  • niclosamide 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.
  • 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.
  • 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”)
  • SARS-CoV severe acute respiratory syndrome
  • Coronaviruses 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.
  • MERS-CoV Middle East respiratory syndrome coronavims
  • SARS-CoV severe acute respiratory syndrome coronavims
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • niclosamide was shown to be a potent anti-neoplastic agent.
  • PLAs 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.
  • niclosamide plasma concentrations in the maximal tolerated dosing cohort i.e., 500 mg TID
  • 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.
  • 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.
  • niclosamide as a potential therapeutic is hindered by its low solubility and dissolution consequently leading to low bioavailability.
  • 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.
  • 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.
  • 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.
  • this study has been shown by this study that the solubility of niclosamide increases with the use of an acidic substance.
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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
  • niclosamide or a pharmaceutically acceptable derivatives thereof such as salts, hydrates and esters, at least one emulsifier targeted to be released in the intestines.
  • the present invention relates to a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • 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 isooct
  • the present invention relates to an enteric coated oral pharmaceutical composition
  • a core having niclosamide or a pharmaceutically acceptable derivatives thereof and at least one emulsifier, and at least one enteric coating 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • an emulsifier such as a sorbitan ester (polysorbate 80) and preferably a dextrin compound such as beta-cyclodextrin or maltodextrin
  • 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.
  • 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.
  • 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
  • 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.
  • a plasticizer which is selected from the group consisting of diethyl phthalate, dimethyl phthalate, dibutyl phthalate, Polyethylene Glycol (PEG), hexadecanol, glycerol triacetate, Lac, octadecanol.
  • 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.
  • 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
  • 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.
  • HLB hydrophilic-lipophilic balance
  • HLB hydrophilic-lipophilic balance
  • 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.
  • 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, Poly
  • 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
  • the emulsifier is preferably polyoxylglycerides or polysorbates or polyethylene glycol derivative.
  • 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
  • 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.
  • cyclodextrins 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.
  • 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.
  • BCD beta cyclodextrin
  • HPBCD hydroxypropyl b-cyclodextrin
  • 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.
  • silica derivatives 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.
  • 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).
  • BET surface area means the surface area of a solid in relation to its mass, measured in m 2 /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).
  • 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.
  • calcium silicate such as Zeopharm
  • magnesium aluminometasilicate such as Neusillin
  • colloidal silicon dioxide most preferably AEROPERL® 300.
  • AEROPERL® 300 a hydrophilic silica derivative
  • the particles of the silica derivative have preferably a mean grain diameter of 10-120 microns.
  • the silica particles have a BET surface area of at least 150 m2/g.
  • the silica particles have a BET surface area of at least 200 m2/g.
  • the silica particles have a BET surface area of at least 250 m2/g.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the weight ratio of niclosamide to the emulsifier(s) is between 1:1 and 1:12, preferably 1:3 to 1:10.
  • 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.
  • 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.
  • 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.
  • BHA butylated hydroxy anisole
  • BHT butylated hydroxy toluene
  • PG propyl gallate
  • TBHQ tert- butyl hydroquinone
  • the composition includes a phenolic antioxidant selected form butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), propyl gallate (PG) and tert- butyl hydroquinone (TBHQ).
  • BHA butylated hydroxy anisole
  • BHT butylated hydroxy toluene
  • PG propyl gallate
  • TBHQ tert- butyl hydroquinone
  • 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.
  • 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
  • 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.
  • sugar alcohols such as sorbitol, xylitol, mannitol, glycerin, etc. and combination thereof.
  • 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.
  • 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.
  • the viscosity-enhancing agent is hydroxypropylmethylcellulose e.g. (HPMC K4M, HPMC K100 LVP; HPMC K15 MP; HPMC E4 MP; HPMC E10 MP CR).
  • compositions of the present invention are to be used for the therapeutic or prophylaxis treatment of viral disease and cancer.
  • 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.
  • composition of the present invention may be used for the treatment or prophylaxis of conditions caused by viruses.
  • 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.
  • 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.
  • 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.
  • niclosamide composition of the present invention is administered with at least one other antiviral compound, and/or at least one antibiotic compound.
  • niclosamide composition of the present invention is administered with at least one other anticancer compound.
  • 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.
  • favipiravir oseltamivir
  • hydroxychloroquine sulphate chloroquine phosphate
  • lopinavir/ritonavir remdesivir
  • interferon alpha and interferon beta azithromycin, budesonide
  • 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.
  • 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.
  • 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.
  • the single unit dose of niclosamide administered with the composition of present invention is between 100 and 300 mg.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.

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Abstract

La présente invention repose sur la découverte inattendue selon laquelle des compositions de niclosamide hautement solubles et biodisponibles peuvent être préparées à une échelle commerciale selon un procédé de fabrication simple. Par conséquent, la présente invention concerne une composition orale entérique comprenant du niclosamide ou ses dérivés pharmaceutiquement acceptables tels que des sels, des hydrates et des esters ciblant la libération intestinale de niclosamide.
PCT/TR2020/050801 2020-04-01 2020-09-03 Libération ciblée de compositions de niclosamide à solubilité et à biodisponibilité élevées WO2021201796A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
TR2020/05165A TR202005165A2 (tr) 2020-04-01 2020-04-01 Yüksek çözünürlüğe ve bi̇yoyararlanima sahi̇p olan ni̇klozami̇d bi̇leşi̇mleri̇
TR2020/05165 2020-04-01
TR2020/06655 2020-04-28
TR2020/06655A TR202006655A2 (tr) 2020-04-01 2020-04-28 Yüksek çözünürlüğe ve bi̇yoyararlanima sahi̇p olan ni̇klozami̇d bi̇leşi̇mleri̇
TR2020/10775A TR202010775A2 (tr) 2020-04-01 2020-07-07 Viral hastalıkların tedavisi için niklozamid
TR2020/10775 2020-07-07

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114288271A (zh) * 2021-12-28 2022-04-08 恒诚制药集团淮南有限公司 一种氯硝柳胺哌嗪盐颗粒剂的制备方法
US11324708B1 (en) 2020-04-01 2022-05-10 UNION therapeutics A/S Niclosamide formulations for treating disease
WO2022169373A1 (fr) * 2021-02-04 2022-08-11 Alan Moana Alexander Compositions de niclosamide ayant une biodisponibilité améliorée
US20230112800A1 (en) * 2021-08-31 2023-04-13 Board Of Regents, The University Of Texas System Delayed release niclosamide formulation
WO2024086629A3 (fr) * 2022-10-19 2024-05-30 Professional Compounding Centers Of America, Ltd. Suspensions pharmaceutiques orales anhydres

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2617049C1 (ru) * 2016-05-12 2017-04-19 Федеральное государственное бюджетное учреждение "Национальный исследовательский центр "Курчатовский институт" Противоопухолевое лекарственное средство на основе никлозамида
WO2019171174A2 (fr) * 2018-03-07 2019-09-12 St Ip Holding Ag Compositions et thérapies combinées comprenant de la 4-méthyl-5-(pyrazin-2-yl) -3h -1,2-dithiole-3-thione, et procédés de fabrication et d'utilisation associés
WO2020028392A1 (fr) * 2018-07-30 2020-02-06 Duke University Analogues de niclosamide et leur utilisation thérapeutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2617049C1 (ru) * 2016-05-12 2017-04-19 Федеральное государственное бюджетное учреждение "Национальный исследовательский центр "Курчатовский институт" Противоопухолевое лекарственное средство на основе никлозамида
WO2019171174A2 (fr) * 2018-03-07 2019-09-12 St Ip Holding Ag Compositions et thérapies combinées comprenant de la 4-méthyl-5-(pyrazin-2-yl) -3h -1,2-dithiole-3-thione, et procédés de fabrication et d'utilisation associés
WO2020028392A1 (fr) * 2018-07-30 2020-02-06 Duke University Analogues de niclosamide et leur utilisation thérapeutique

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DEVARAKONDA, B. HILL, R.A. LIEBENBERG, W. BRITS, M. DE VILLIERS, M.M.: "Comparison of the aqueous solubilization of practically insoluble niclosamide by polyamidoamine (PAMAM) dendrimers and cyclodextrins", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 304, no. 1-2, 4 November 2005 (2005-11-04), NL , pages 193 - 209, XP005106646, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2005.07.023 *
LODAGEKAR ANURAG; BORKAR ROSHAN M.; THATIKONDA SOWJANYA; CHAVAN RAHUL B.; NAIDU V.G.M.; SHASTRI NALINI R.; SRINIVAS R.; CHELLA NAV: "Formulation and evaluation of cyclodextrin complexes for improved anticancer activity of repurposed drug: Niclosamide", CARBOHYDRATE POLYMERS, APPLIED SCIENCE PUBLISHERS , LTD BARKING, GB, vol. 212, 1 January 1900 (1900-01-01), GB , pages 252 - 259, XP085615349, ISSN: 0144-8617, DOI: 10.1016/j.carbpol.2019.02.041 *
MICHAEL T SCHWEIZER, KATHLEEN HAUGK 3, JOŽEFA S MCKIERNAN 4, ROMAN GULATI 5, HEATHER H CHENG 1 2, JESSICA L MAES 6, RUTH F DUMPIT : "A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer", PLOS ONE, vol. 13, no. 6, 1 June 2018 (2018-06-01), pages e0198389-1 - e0198389-12, XP055936588 *
VISHWAS PARDHI, RAHUL B CHAVAN, RAJESH THIPPARABOINA , SOWJANYA THATIKONDA , VGM NAIDU , NALINI R SHASTRI : "Preparation, characterization, and cytotoxicity studies of niclosamide loaded mesoporous drug delivery systems", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 528, no. 1-2, 7 August 2017 (2017-08-07), pages 202 - 214, XP055936585 *
XIAXIA SHEN; DENGGUANG YU; LIMIN ZHU; CHRISTOPHER BRANFORD-WHITE; KENNETH WHITE; NICHOLAS P. CHATTERTON;: "Electrospun diclofenac sodium loaded EudragitL 100-55 nanofibers for colon-targeted drug delivery", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 408, no. 1, 26 January 2011 (2011-01-26), NL , pages 200 - 207, XP028159259, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2011.01.058 *
XU JIMIN, SHI PEI-YONG, LI HONGMIN, ZHOU JIA: "Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential", ACS INFECTIOUS DISEASES, AMERICAN CHEMICAL SOCIETY, US, vol. 6, no. 5, 8 May 2020 (2020-05-08), US , pages 909 - 915, XP055796707, ISSN: 2373-8227, DOI: 10.1021/acsinfecdis.0c00052 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11324708B1 (en) 2020-04-01 2022-05-10 UNION therapeutics A/S Niclosamide formulations for treating disease
WO2022169373A1 (fr) * 2021-02-04 2022-08-11 Alan Moana Alexander Compositions de niclosamide ayant une biodisponibilité améliorée
US20230112800A1 (en) * 2021-08-31 2023-04-13 Board Of Regents, The University Of Texas System Delayed release niclosamide formulation
CN114288271A (zh) * 2021-12-28 2022-04-08 恒诚制药集团淮南有限公司 一种氯硝柳胺哌嗪盐颗粒剂的制备方法
WO2024086629A3 (fr) * 2022-10-19 2024-05-30 Professional Compounding Centers Of America, Ltd. Suspensions pharmaceutiques orales anhydres

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