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WO2021245700A2 - Compositions pharmaceutiques lipidiques de remdésivir - Google Patents

Compositions pharmaceutiques lipidiques de remdésivir Download PDF

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Publication number
WO2021245700A2
WO2021245700A2 PCT/IN2021/050536 IN2021050536W WO2021245700A2 WO 2021245700 A2 WO2021245700 A2 WO 2021245700A2 IN 2021050536 W IN2021050536 W IN 2021050536W WO 2021245700 A2 WO2021245700 A2 WO 2021245700A2
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WO
WIPO (PCT)
Prior art keywords
remdesivir
pharmaceutical composition
weight
amount
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2021/050536
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English (en)
Other versions
WO2021245700A3 (fr
Inventor
Indranil Nandi
Tusharmouli Mukherjee
Nilesh Jaiswal
Dinesh Kumar
Rakesh Kumar Singh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jubilant Generics Ltd
Original Assignee
Jubilant Generics Ltd
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Publication date
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Publication of WO2021245700A2 publication Critical patent/WO2021245700A2/fr
Publication of WO2021245700A3 publication Critical patent/WO2021245700A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to pharmaceutical lipid compositions of remdesivir or its pharmaceutically acceptable salts or solvates thereof.
  • the present invention provides pharmaceutical oral lipid compositions comprising remdesivir and process for preparing these compositions.
  • the compositions as per the present invention are useful for treating and/or preventing viral infections including coronavirus infections (SARS CoV-2, also called COVID-19).
  • Remdesivir is known to exhibit antiviral properties.
  • Remdesivir is a single stereoisomer monophosphoramidate prodrug of a nucleoside analog, used for the treatment of coronavirus disease.
  • Remdesivir is chemically known as 2-Ethylbutyl (2S)-2- ⁇ [(S)- ⁇ [(2R,3S,4R,5R)-5-
  • Remdesivir is presently approved in many countries only in the form of an injectable dosage form in the strength of 100 mg by Gilead Sciences for the treatment of infection caused by coronavirus disease 2019 (COVID-19).
  • Remdesivir is not the first choice for oral delivery due to poor water-solubility, poor dissolution, and poor oral bioavailability due to hepatic instability, which results in its complete first-pass clearance.
  • These undesirable physicochemical characteristics pose significant technical challenges to formulation scientists in the development of a suitable oral formulation with desired technical attributes.
  • PCT Patent Publication No. WO2016/069826 assigned to Gilead Sciences discloses remdesivir as a compound per se and its manufacturing process and further discloses the use of remdesivir in the treatment of Filoviridae infection.
  • US Patent Publication No. US2019/0255085 assigned to Gilead Sciences discloses the use of remdesivir in the treatment of Coronaviridae infection in a human.
  • US Patent Publication No. US2018/346504 assigned to Gilead Sciences discloses crystalline polymorphic forms of remdesivir. This patent publication further discloses crystalline polymorphs form I to form IV, mixtures of crystalline forms and maleate form I of remdesivir.
  • US Patent Publication No. US2019/083525 assigned to Gilead Sciences discloses remdesivir injectable composition comprising cyclodextrin and pH adjusting agents.
  • compositions based on lipid drug delivery system offers an extensive variety of formulation approaches such as solutions, suspensions, emulsions, solid dispersions, and self-emulsifying drug delivery systems (SEDDS).
  • Formulation technologies like emulsion and self-emulsifying drug delivery systems (SEDDS) are known to improve the bioavailability of drug molecules. Depending upon the size, they are called self-micro emulsifying drug delivery system (SMEDDS) or self-nano emulsifying drug delivery system (SNEDDS).
  • SMEDDS self-micro emulsifying drug delivery system
  • SNEDDS self-nano emulsifying drug delivery system
  • This technology comprises an isotropic mixture of drug, oil, surfactant, and/or co- surfactant, which after oral administration gets emulsified in the aqueous media in the gastrointestinal tract.
  • remdesivir is approved only in injection form.
  • the injection would be required to be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care which requires huge and advanced medical infrastructure and set-ups, which is highly challenging for least developed countries and countries having a significant geographical area and large population.
  • the dose of remdesivir injection is 200 mg on day 1, followed by once-daily maintenance doses of 100 mg from day 2.
  • administration of remdesivir injection in hospitalized patients is again a big challenge and accordingly requires trained and highly skilled medical professionals.
  • the said injection is administered only via intravenous infusion within 30 to 120 minutes.
  • the treatment duration is usually for 5 days and may be extended up to 5 additional days (10 days total) if clinical improvement is not observed. Thus, the whole process may be undesirable to patients due to low patient compliance.
  • the injection dosage form also requires special storage conditions, which not only require specialized infrastructure but also increases the product cost.
  • lipid compositions as per the present invention can be manufactured by simple, reproducible, and commercially viable processes in a pharmaceutical laboratory as well as at an industrial scale.
  • the prepared dosage forms are suitable for the treatment of viral infections including COVID-19 infection.
  • the present invention relates to oral lipid compositions comprising remdesivir or its pharmaceutically acceptable salts or solvate thereof as an active agent and at least one or more pharmaceutically acceptable excipients and process for preparing such compositions.
  • the present invention also relates to self-emulsifying oral pharmaceutical compositions comprising remdesivir as an active agent and at least one or more pharmaceutically acceptable excipients and processes for preparing such compositions.
  • the present invention also relates to the use of oral lipid compositions comprising remdesivir in the manufacture of a medicament for treating viral infections such as Arenaviridae, Coronaviridae (including COVID-19 infection), Filoviridae, Flaviviridae, or Paramyxoviridae viral infections.
  • viral infections such as Arenaviridae, Coronaviridae (including COVID-19 infection), Filoviridae, Flaviviridae, or Paramyxoviridae viral infections.
  • composition or “dosage form” or “drug delivery system”, as in pharmaceutical composition, is intended to encompass an oral lipid drug product comprising remdesivir and other inert ingredient(s) (pharmaceutically acceptable excipients).
  • the pharmaceutical composition of the invention include, but is not limited to, powder, granules, concentrate, pellets, beads, powder, or granule formulation for compounding to produce a reconstituted liquid composition, tablets, capsules (hard and soft or liquid-filled soft gelatin capsules), pills, troches, sachets, microcapsules, mini-tablets, tablets in capsules, microspheres, matrix composition, gel, paste, liquid dosage forms such as solution, suspension, emulsion, microemulsion, nanoemulsion, pickering emulsion, self-emulsifying dosage form, self-micro emulsifying dosage form, self-nano emulsifying dosage form, vesicular systems such as liposomes, niosomes, pharmacosomes, phytosomes, transfersomes, ethosomes, herbosomes, colloidosomes, archaeosomes, vesosomes and the like, lipid-based particulate system such as lipospheres, solid
  • the drug delivery system of the invention is a liquid dosage form and may be filled into a capsule such as a soft gelatin capsule, a hard gelatin capsule, or a hydroxypropylmethylcellulose capsule.
  • the drug delivery system of the invention is ready to use liquid dosage form to be administered directly or liquid dosage form to be administered after reconstitution with a suitable vehicle.
  • the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. Unless otherwise stated the weight percentages expressed herein are based on the final weight or volume of the composition. As used herein, the term “about” means ⁇ approximately 20% of the indicated value, such that "about 10 percent” indicates approximately 08 to 12 percent. As used herein, the term “remdesivir” is used in a broad sense to include not only “remdesivir” per se (free base) but also its pharmaceutically acceptable salts, solvates, esters, hydrates, metabolites, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof.
  • Polymorph may refer to various crystalline and amorphous forms of remdesivir, which can be characterized by methods such as melting point, X-ray diffraction pattern, Raman spectra, IR spectra, or any other method known in the art. Remdesivir and its nucleoside analog/metabolite GS-441524 are covered under the scope of the present invention.
  • excipient means a pharmacologically inactive component such as diluents, binders, disintegrants, lubricants, solubilizers, glidants, surfactants, co-surfactants, oil phase, solid carriers, polymers, emulsifiers, thickening agents, antioxidants, viscosity modifiers, preservatives, stabilizers, pH modifiers, gelling agents, flavoring agents, taste masking agents, coloring agents, sweeteners, vehicles, antacids, cryoprotectants, lyoprotectants and the like and any combination thereof.
  • pharmacologically inactive component such as diluents, binders, disintegrants, lubricants, solubilizers, glidants, surfactants, co-surfactants, oil phase, solid carriers, polymers, emulsifiers, thickening agents, antioxidants, viscosity modifiers, preservatives, stabilizers, pH modifiers, gelling agents, flavoring agents, taste mask
  • self-emulsifying (SEDDS) drug delivery refers to stable isotropic mixtures of at least active ingredient(s), oil(s), surfactant(s), and co-surfactant(s) and/or other pharmaceutical excipients.
  • Self-emulsifying delivery systems are categorized as self-micro emulsifying drug delivery systems (SMEDDS) and self-nano emulsifying drug delivery systems (SNEDDS).
  • emulsion formulations of the invention can be designed to be oil in water type (o/w), water in oil (w/o) type, multiple phasic and self-emulsifying drug delivery systems (SEDDS), which will further be categorized as emulsion, self-micro emulsifying drug delivery systems (SMEDDS) or self-nano emulsifying drug delivery systems (SNEDDS).
  • SMEDDS self-micro emulsifying drug delivery systems
  • SNEDDS self-nano emulsifying drug delivery systems
  • emulsion droplets may have an average or mean droplet size of from 1 micron to 500 microns, preferably less than 400 microns, 300 microns, 200 microns, and less than 100 microns. More preferably, emulsion droplets may have an average or mean droplet size of from 1 micron to 30 microns.
  • droplets may have an average droplet size less than about 1000 nm, preferably less than 800 nm, preferably less than 500 nm, more preferably less than 300 nm, more preferably less than 200 nm, more preferably less than 100 nm, and smaller ranges encompassed therein.
  • average or “mean” particle/droplet size refers to the volume average diameter of the droplets formed upon emulsification of the self-emulsifying drug delivery system.
  • the droplet size and zeta potential of the emulsion as per the present invention can be determined by Zetasizer or any other method known in the art.
  • stable refers to chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40°C and 75% relative humidity (R.H.) or at 25°C and 60% R.H. for a period of at least one month, particularly for a period of two months, and more particularly for a period of at least three months.
  • R.H. relative humidity
  • the purity of remdesivir in compositions as per the present invention ranges from at least 99.99%, 99%, 98%, 97%, 96%, or 95%.
  • the pharmaceutical compositions of the present invention comprise about 1 mg to about 1000 mg of remdesivir. Preferably, from about 1 mg to about 500 mg of remdesivir.
  • the dosage administered orally may conveniently be in the range of between about 2.5 mg to about 100 mg.
  • the dose may be administered one or more times a day (such as from one to ten times per day).
  • the composition is self- administered by a patient in a daily dose of from about 20 mg to about 200 mg.
  • the pharmaceutical compositions of the present invention include particle size of remdesivir, having a particle size distribution such that D90 is less than about 200 pm, D50 is less than about 100 pm and Dio is less than about 50 pm.
  • particle size distribution is D90 is less than about 100 pm, D50 is less than about 70 pm and Dio is less than about 30 pm.
  • the particle size of remdesivir can be measured by suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy, and any other technique known in the art.
  • the present invention relates to the oral lipid compositions of remdesivir and the method of manufacturing such compositions.
  • the present invention also relates to oral lipid compositions comprising remdesivir as an active agent and at least one or more pharmaceutically acceptable excipients and processes for preparing such compositions.
  • the present invention relates to self-emulsifying pharmaceutical compositions of remdesivir and the method of manufacturing such compositions.
  • the present invention also relates to self-emulsifying oral pharmaceutical compositions comprising remdesivir and at least one or more pharmaceutically acceptable excipients selected from oil, surfactant/emulsifier, and/or co- surfactant.
  • the pharmaceutical composition is in the form of a tablet or a capsule dosage form. In another embodiment of the invention, the pharmaceutical composition is in the form of a powder or granule dosage form for reconstitution before oral administration. In another embodiment of the invention, the pharmaceutical composition is in the form of the liquid dosage form. In another embodiment of the invention, the pharmaceutical composition is in the form of the ready-to-use liquid dosage form. In another embodiment of the invention, the pharmaceutical composition is in the form of the liquid dosage form filled in soft-gelatin capsules. In another embodiment of the invention, the pharmaceutical composition is a liquid emulsion dosage form.
  • oral lipid pharmaceutical compositions comprising remdesivir as an active agent and at least one or more pharmaceutically acceptable excipients, like diluent, binder, disintegrant, lubricant, solubilizer, glidant, surfactant, co- surfactant, oil phase, carrier, emulsifier, thickening agent, preservative, flavoring agent, taste masking agent, antioxidant, stabilizer, viscosity modifier, coloring agent, pH modifier, gelling agent, sweetener, vehicle, antacid, cryoprotectant, and lyoprotectant.
  • the present invention provides a stable remdesivir composition in the form of an emulsion.
  • the composition that can be packed in larger bottles for many doses such as multi-dose bottles.
  • a pharmaceutical composition in the liquid form comprising remdesivir, an oil phase or carrier, surfactant, emulsifier, thickening agent, antioxidant, preservative, flavoring agent, sweetening agent, one or more vehicles, and one or more other pharmaceutically acceptable excipients.
  • an oral liquid lipid pharmaceutical composition comprising: a) remdesivir, b) emulsifier, c) antioxidant, d) flavoring agent, and e) one or more pharmaceutically acceptable vehicles.
  • an oral liquid lipid pharmaceutical composition comprising: a) remdesivir, b) emulsifier, c) oil phase, d) thickening agent, e) antioxidant, f) flavoring agent and g) one or more pharmaceutically acceptable vehicles.
  • the composition further comprises one or preservatives and sweetening agents.
  • an oral lipid pharmaceutical composition comprising remdesivir and at least one or more pharmaceutically acceptable excipients, wherein the pH of the composition is in the range of 2 to 9.
  • the pH of the composition is in a range of 2 to 8, and in a range of 3 to 8. More preferably, the pH of the composition is in a range of 3.0 to 6.5 and in a range of 3.5 to 6.5.
  • an oral lipid pharmaceutical composition comprising remdesivir, wherein the total impurities/related substances are not more than 2% when the composition is stored at 40°C/75% RH for a period of at least 1 month.
  • an oral lipid pharmaceutical composition comprising remdesivir, wherein the composition is easily pourable and when shaken has a viscosity in the range of 100 to 5000 cPs at 25°C.
  • the viscosity is in the range of 10 to 2500 cPs at 25°C.
  • the viscosity is in the range of 10 to 1500 cPs at 25°C. More particularly, the viscosity is in the range of 10-500 cps at 25°C or 10-400 cps at 25°C.
  • the viscosity can be measured by using a suitable instrument such as Brookfield viscometer and Haake VT 550 viscometer at room temperature (25°C).
  • the pharmaceutical composition as per the present invention provides a pharmaceutical composition, in which the bitter taste of remdesivir is masked by one or more taste masking agents, flavoring agents, and/or sweetening agents.
  • Organoleptic properties of the compositions were evaluated for texture, taste, after taste, odor, flavor, and acceptability. The compositions were perceived to have good overall acceptability based on tested organoleptic properties.
  • the pharmaceutical composition comprising remdesivir in an amount of from about 1% to about 97% by weight and at least one or more pharmaceutically acceptable excipients.
  • the amount of remdesivir is in the range of about 5% to about 85% by weight of the composition.
  • the oral lipid pharmaceutical composition comprises at least 5%, preferably at least 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% more preferably at least 10% by weight of the remdesivir.
  • an oral lipid pharmaceutical composition comprising remdesivir and at least one or more pharmaceutically acceptable excipients, wherein the amount of remdesivir ranges from about 0.1 mg/mL to about 400 mg/mL. In another embodiment, the amount of remdesivir ranges from about 0.1 mg/mL to about 200 mg/mL.
  • the amount of remdesivir in the liquid composition ranges preferably from about 0.5 mg/mL to 300 mg/mL, preferably from about 0.5 mg/mL to 200 mg/mL, preferably from about 0.5 mg/mL to 100 mg/mL. More preferably the amount of remdesivir ranges from about 0.5 mg/mL to 30 mg/mL.
  • an oral lipid pharmaceutical composition comprising remdesivir and at least one or more pharmaceutically acceptable excipients, wherein the amount of remdesivir is lmg/mL, 2mg/mL, 25mg/5mL, 50mg/5mL, 100mg/5mL, 200mg/5ml and 250mg/5mL, 5mg/mL, 25mg/mL, 20mg/ml, 50mg/mL, lOOmg/mL and 250mg/mL. Particularly, the amount of remdesivir is 100mg/5mL.
  • the oral lipid composition comprising: a) remdesivir in an amount of about 1% to about 97% by weight, b) oil phase in an amount of 0 to about 70% by weight, c) surfactant in an amount of 0 to about 50% by weight, d) co-surfactant in an amount of 0 to about 50% by weight, and e) optionally one or more pharmaceutically acceptable excipients.
  • the oral lipid composition comprising: a) remdesivir in an amount of about 1% to about 97% by weight, b) emulsifier in an amount of about 0.01% to about 50% by weight, and c) optionally one or more pharmaceutically acceptable excipients.
  • the oral lipid composition comprising: a) remdesivir in an amount of about 1% to about 97% by weight, b) oil phase in an amount of 0 to about 70% by weight, c) surfactant in an amount of 0 to about 50% by weight, d) co-surfactant in an amount of 0 to about 50% by weight, e) optionally one or more pharmaceutically acceptable excipients and f) water.
  • the oral lipid pharmaceutical composition comprising: a) remdesivir in an amount of about 0.001% to about 85% by weight, b) oil phase in an amount of 0 to about 60% by weight, c) emulsifier in an amount of 0 to about 40% by weight, d) thickening agent in an amount of 0 to about 20% by weight, e) antioxidant in an amount of 0 to about 30% by weight, f) flavoring agent in an amount of 0 to about 20% by weight, g) one or more vehicles in an amount of 0 to about 90% by weight and optionally one or more pharmaceutically acceptable excipients.
  • the oral lipid pharmaceutical composition comprising: a) remdesivir in an amount of about 0.001% to about 85% by weight, b) emulsifier in an amount of 0 to about 40% by weight, c) flavoring agent in an amount of about 0 to about 20% by weight, d) sweetening agent in an amount of about 0 to about 20% by weight, e) one or more vehicles in an amount of 0 to about 70% by weight and optionally one or more pharmaceutically acceptable excipients.
  • the self-emulsifying oral pharmaceutical composition comprising: a) remdesivir in an amount of about 5% to about 85% by weight, b) oil phase in an amount of about 0.01% to about 60% by weight, c) surfactant in an amount of about 0.01% to about 40% by weight, d) co-surfactant in an amount of about 0.01% to about 40% by weight, and e) optionally one or more pharmaceutically acceptable excipients selected from the group consisting of solubilizer, diluent, binder, disintegrant, glidant, lubricant, solid carrier, buffering agent, and stabilizing agent.
  • the oral lipid composition comprising: a) remdesivir in an amount of about 10% to about 90% by weight, b) PEG caprylic/capric glycerides in an amount of 0 to about 30% by weight, c) propylene glycol caprylate/caprate in an amount of 0 to about 30% by weight, d) propylene glycol monolaurate in an amount of 0 to about 20% by weight, e) glyceryl monooleate in an amount of 0 to about 50% by weight, f) D -a-Tocopherol polyethylene glycol 1000 succinate in an amount of about 1% to about 15% by weight, g) diethylene glycol monoethyl ether in an amount of about 1% to about 10% by weight, h) glyceryl monostearate in an amount of about 1% to about 10% by weight, and i) optionally one or more pharmaceutically acceptable excipients.
  • the oral lipid pharmaceutical composition comprising: a) remdesivir in an amount of about 1% to about 85% by weight, b) oil phase in an amount of 0.01% to about 30% by weight, c) emulsifier in an amount of 0.01% to about 30% by weight, d) thickening agent in an amount of 0.01% to about 20% by weight, and e) antioxidant in an amount of about 0.01% to about 30% by weight, f) flavoring agent in an amount of about 0.01% to about 20% by weight, g) one or more vehicles in an amount of about 0.001% to about 90% by weight and optionally one or more pharmaceutically acceptable excipients.
  • the composition is an oral liquid lipid composition.
  • the oral lipid pharmaceutical composition comprising: a) remdesivir in an amount of about 1% to about 85% by weight, b) emulsifier in an amount of 0.01% to about 40% by weight, c) flavoring agent in an amount of about 0.01% to about 20% by weight, d) sweetening agent in an amount of about 0.01% to about 20% by weight, e) preservative in an amount of about 0.01% to about 10% by weight, f) one or more vehicles in an amount of 0.001% to about 90% by weight and optionally one or more pharmaceutically acceptable excipients.
  • the oral lipid pharmaceutical composition comprising: a) remdesivir in an amount of about 0.01% to about 20% by weight, b) oil phase in an amount of 0.01% to about 20% by weight, c) antioxidant in an amount of about 0.01% to about 20% by weight, d) flavoring agent in an amount of about 0.01% to about 10% by weight, e) one or more vehicles in an amount of 0.001% to about 90% by weight and optionally one or more pharmaceutically acceptable excipients.
  • the oral lipid pharmaceutical composition comprising: a) remdesivir in an amount of about 0.01% to about 20% by weight, b) thickening agent in an amount of 0.01% to about 10% by weight, c) emulsifier in an amount of 0.01% to about 20% by weight, d) flavoring agent in an amount of about 0.01% to about 10% by weight, e) one or more vehicles in an amount of 0.001% to about 90% by weight and optionally one or more pharmaceutically acceptable excipients.
  • the oral lipid pharmaceutical composition comprising: a) remdesivir in an amount of about 0.01% to about 20% by weight, b) emulsifier in an amount of 0.01% to about 20% by weight, c) sweetening agent in an amount of about 0.01% to about 20% by weight, d) flavoring agent in an amount of about 0.01% to about 10% by weight, e) preservative in an amount of about 0.01% to about 10% by weight, f) one or more vehicles in an amount of 0.001% to about 90% by weight and optionally one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising remdesivir and an emulsifier, wherein the ratio of the weight of remdesivir to the weight of the emulsifier is from 10:0.05 to 0.05:10. In an embodiment, the ratio of the weight of the remdesivir to the weight of the emulsifier is 1:0.2 to 1:5. In an embodiment, the ratio is 1:0.5 to 1:5. In an embodiment, the ratio of the weight of the remdesivir to the weight of the emulsifier is 1:1.
  • a pharmaceutical composition comprising remdesivir and an oil phase, wherein the ratio of the weight of remdesivir to the weight of the oil phase is from 10:0.05 to 0.05:10. In an embodiment, the ratio of the weight of the remdesivir to the weight of the oil phase is 1:0.2 to 1:5. In an embodiment, the ratio of the weight of the remdesivir to the weight of the oil phase is 1:1 or 1:0.5.
  • the oral lipid pharmaceutical compositions are prepared by dry blending, dry mixing, simple mixing, wet granulation, dry granulation such as slugging or compaction, lyophilization, or direct compression or based on multi-unit particulate technology.
  • the oral lipid composition comprising remdesivir as an active agent and at least one or more pharmaceutically acceptable excipients, prepared by the following process, mixing remdesivir to an oil phase, surfactant, co-surfactant to form a homogenous dispersion.
  • the oral lipid composition is prepared by the following process, mixing remdesivir to an oil phase, surfactant, co surfactant, and water to form an emulsion, micro-emulsion, or nano-emulsion.
  • the lipid compositions for oral administration comprising remdesivir as an active agent and at least one or more pharmaceutically acceptable excipients, prepared by heating and mixing the oil, surfactant, and co-surfactant.
  • the prepared mixture is then gently mixed for making the homogeneous formulation dispersion.
  • the pre-concentrate is ready for encapsulation, which will form in situ emulsion upon contact with biological fluid upon administration by the patient.
  • the lipid compositions for oral administration comprising remdesivir as an active agent and at least one or more pharmaceutically acceptable excipients, prepared by a) mixing of one or more vehicles and thickening agents, b) heating the liquid of step a) to form a clear solution, c) adding one or more oil and/or emulsifier to the solution of step b), d) adding one or more vehicles to the solution of step c) followed by addition of drug, e) heating the liquid of step d) at a suitable temperature to form clear solution and stir to dissolve completely, f) addition of suitable taste masking agent and/or flavoring agent and/or sweetening agent to the solution of step e) and stir to dissolve completely.
  • oral lipid pharmaceutical compositions comprising remdesivir and at least one or more pharmaceutically acceptable excipients, wherein the composition is stable.
  • the composition is stable for at least one month while stored at 40° ⁇ 2°C and 75+5% relative humidity.
  • compositions wherein the composition has an assay in the range from 90% to 110% as measured by HPLC (High- Performance Liquid Chromatography) method using a suitable column.
  • HPLC High- Performance Liquid Chromatography
  • the compositions as described herein exhibits an assay amount of at least 95.0% initially or after one to two months while stored at 40° ⁇ 2°C and 75+5% relative humidity.
  • the oral lipid pharmaceutical compositions of the present invention are able to form in-situ homogeneous, thermodynamically stable, and uniform droplet sizes clear emulsion.
  • lipid compositions have excellent water mixing properties.
  • the drug delivery system according to the invention is liquid and forms a microemulsion when contacted with an aqueous medium such as a gastrointestinal fluid, e.g. gastric juice.
  • the present invention provides a pharmaceutical composition that gives a quick-release, also capable of achieving rapidly maximum drug levels in the plasma and which exhibits desired pharmaceutical technical attributes such as pH, solubility, viscosity, dispersibility, droplet size, phase-separation, cloud point, refractive index, zeta potential, percent transmittance, dissolution, assay, temperature stability, stability, and bioavailability.
  • Bioavailability refers to the proportion of the drug administered that reaches the physiological site where the drug exerts its therapeutic effect, which is generally regarded as the bloodstream for many drugs.
  • the composition provides a pharmacokinetic profile substantially equivalent to the pharmacokinetic profile of intravenous injectable dosage form comprising remdesivir.
  • oral lipid pharmaceutical compositions comprising remdesivir and at least one or more pharmaceutically acceptable excipients, wherein remdesivir has a particle size distribution D9oless than about 100 pm, D5oless than about 50 pm, and Dio less than about 20 pm.
  • oral lipid pharmaceutical compositions comprising remdesivir and at least one or more pharmaceutically acceptable excipients, wherein the composition has droplet size from 1 micron to 100 microns.
  • the composition has droplet size D90 from 1 micron to 100 microns.
  • the composition has droplet size D50 from 1 micron to 50 microns.
  • the composition has droplet size Dio from 1 micron to 20 microns.
  • the composition has droplet size D90 of about 20 microns, D50 of about 10 microns, and Dio of about 2 microns.
  • oral lipid compositions of remdesivir surprisingly result in an increased dissolution rate.
  • the compositions exhibit at least 75% of the drug release in 15 minutes in 900 ml of Mcllvaine Buffer (pH 3.0), using a USP II apparatus (paddle) at a temperature of 37+0.5°C and a rotation speed of 50 revolutions per minute.
  • compositions of the present invention may be packaged in HDPE bottles, glass bottles, or blister packs together with instructions to administer the dosage form.
  • the compositions may be taken in measured doses using a container, cup, straw, spoon, syringe, dispensing syringe, dosing syringe, or any other suitable device.
  • oral lipid compositions of the present invention in the manufacture of a medicament for treating viral infections such as Arenaviridae, Coronaviridae (such as SARS, MERS, 229E, OC43, HKU1, NL63, and COVID-19), Filoviridae (such as Ebola virus (EBOV) and Marburg vims (MARV)), Flaviviridae, or Paramyxoviridae viral infections.
  • viral infections such as Arenaviridae, Coronaviridae (such as SARS, MERS, 229E, OC43, HKU1, NL63, and COVID-19), Filoviridae (such as Ebola virus (EBOV) and Marburg vims (MARV)), Flaviviridae, or Paramyxoviridae viral infections.
  • the present invention provides the use of pharmaceutical compositions in the treatment of coronavirus disease 2019 (COVID-19) infection.
  • the composition can be administered once daily or divided into multiple daily doses from once per day to once in six months such as twice daily, three times daily, four times daily, five times daily, once a week, twice in a week, thrice in a week, once in two weeks, once in three weeks, once in four weeks or the like.
  • the composition is administered at least three times a day.
  • the compositions of the present invention can be given to diabetic patients because the composition is free of sugar.
  • the pharmaceutical compositions as per the present invention are meant for pre-hospitalization use.
  • pharmaceutical compositions as per the present invention avoid requirements of specialized infrastructure set-up, hospital settings, trained professional personnel, and any special storage conditions, and accordingly are cost-efficient.
  • the methods provided herein comprise co-administering remdesivir with one or two or more active drugs with an anti-viral vaccine, other antiviral drugs, antibiotics, antifungals, anti-inflammatories, protease inhibitors, JAK inhibitors, or other nucleoside or non-nucleoside antiviral drugs, which can be dosed orally.
  • the compositions comprise a combination of remdesivir and baricitinib.
  • the oral liquid compositions comprise a combination of remdesivir and baricitinib.
  • oils according to the present invention include, but not limited to, long-chain fatty acids, long, medium and short-chain mono-, di-, or triglycerides (including Cs-Cio), propylene glycol esters or a mixture thereof, propylene glycol esters of fatty acids, propylene glycol monocaprylate, beeswax, soy fatty acids, edible oils such castor oil, arachis oil, cottonseed oil, corn oil, olive oil, corn oil mono-di-triglycerides, hydrogenated vegetable oil, soyabean oil, hydrogenated soyabean oil, sesame oil, sweet orange oil, sunflower seed oil, peanut oil, coconut oil, palm seed oil, canola oil, rapeseed oil and oleic acid, oils and essential oils such as peppermint oil, rosemary oil, orange oil, lemon oil, tea tree oil, wintergreen oil, lavender oil, ginger oil, nutmeg oil, fennel oil, eucalyptus oil, rosemary oil
  • this list of essential oils further includes pomegranate seed oil, black cumin oil, rice germ oil, rice bran oil, krill oil, and green-lipped muscle oil, commercially available oils such as Oleyl Erucate, Propylene Glycol Dicaprate, Propylene Glycol Dicaprylocaprate, Propylene Glycol Dicaprylate/Dicaprate, Glyceryl Tricaprylate/Tricaprate, Caprylic/Capric Triglyceride, Caprylic/Capric/Linoleic Triglyceride, Caprylic/Capric/Succinic Triglyceride, PEG 300 oleic glycerides (Labrafil M-1944CS), PEG 300 linoleic glycerides (Labrafil M-2125CS).
  • oils such as Oleyl Erucate, Propylene Glycol Dicaprate, Propylene Glycol Dicaprylocaprate, Propylene Glycol Dicaprylate/Dicaprate, Glyceryl Tri
  • oil phase can be interchangeable with the term ‘lipid’ or “surfactant” or “emulsifier”.
  • the oil phase may constitute from about 0.01% to about 90% by weight of the composition.
  • the oil phase according to the present invention is present in an amount of about 90% or less, e.g. 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less.
  • Various useful surfactants or emulsifiers include, but not limited to, sodium lauryl sulphate, polysorbates (such as Tween 20, Tween 80), cetrimide, cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, lecithin, poly ethylene glycols, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monolaurate (Span 20), polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, corn oil mono-di-triglycerides, polyoxyethylene polyoxypropylene block copolymers such as poloxamers, sorbitan monooleate (Span 80), polyoxyl 35 castor oil (
  • surfactant can be interchangeable with the term “co surfactant”, “emulsifier”, “oil-phase”, or “solubilizer” or “co-solubilizer”.
  • the amount of surfactant or emulsifier according to the present invention ranges from about 0% to about 80% by weight of the composition.
  • the surfactant or emulsifier according to the present invention is present in an amount of about 80% or less, e.g. 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less.
  • Suitable co-surfactant according to the present invention include, but not limited to, glycol ethers such as polysorbates (including Tween 20, Tween 80), sorbitan monooleate (Span 80), tetraglycol, polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH40), polyoxyl 60 hydrogenated castor oil (Cremophor RH60), a triglyceride or a derivative thereof, glycofurol (e.g., tetrahydrofurfuryl PEG ether), pyrrolidine derivatives such as N-methyl pyrrolidone (e.g., Pharmasolve ® ) and 2-pyrrolidone (e.g., Soluphor ® P), short chain alcohols comprising from 1 to 6 carbons (e.g., ethanol), benzyl alcohol, alkane diols and trials (e.g, propylene glycol and its derivatives,
  • co-surfactant can be interchangeable with the term “surfactant”, “emulsifier”, co-emulsifier”, “solubilizer” or “co-solubilizer”.
  • the amount of co-surfactant according to the present invention ranges from 0 to about 80% by weight of the composition. In an embodiment, the co-surfactant according to the present invention is present in an amount of about 80% or less, e.g. 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 2% or less.
  • Suitable solvents or vehicles according to the present invention include aqueous or organic solvents including, but are not limited to, water, water for injection, esters such as ethyl acetate, methyl acetate, isopropyl acetate, ketones such as acetone, diacetone, methyl ethyl ketone, methyl n-butyl ketone, N,N-dimethylformamide, polyols, polyethers, oils, castor oil, alkyl ketones, methylene chloride, alcohols such as methanol, ethanol, acidified ethanol, isopropanol, butanol, cetyl alcohol, dichloromethane, chloroform, dimethyl acetamide, dimethyl sulfoxide, ether, diethyl ether, glycerin, propylene glycol, ethylene glycol, polyethylene glycol (such as PEG 400), dimethylisosorbide, polysorbates, dibutyl sebacate, phthalic acid est
  • Various useful fillers or diluents include, but are not limited to microcrystalline cellulose ("MCC”), sodium alginate, silicified MCC, microfine cellulose, lactitol, cellulose acetate, kaolin, glucose, lactose, maltose, fructose, sucrose, trehalose, starch, pregelatinized starch, mannitol, xylitol, maltitol, sorbitol, dextrates, dextrin, maltodextrin, compressible sugar, confectioner’s sugar, dextrose, polydextrose, simethicone, calcium carbonate, calcium sulfate, calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, isomalt, and mixtures thereof.
  • MCC microcrystalline cellulose
  • silicified MCC microfine cellulose
  • lactitol cellulose acetate
  • kaolin glucose
  • the amount of diluent according to the present invention ranges from 0 to about 90% by weight of the composition. In an embodiment, the diluent according to the present invention is present in an amount of about 90% or less, 80% or less, e.g. 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less.
  • binders or thickening agents include, but are not limited to acacia, guar gum, xanthan gum, alginic acid, sodium alginate, dextrin, carbomer, maltodextrin, methylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose, carboxymethyl cellulose sodium, cottonseed oil, povidone, ceratonia, dextrose, polydextrose, starch, gelatin, pregelatinized starch, hydrogenated vegetable oil type I, maltodextrin, polyethylene oxide, poly methacrylates and mixtures thereof.
  • the amount of binder or thickening agents according to the present invention ranges from 0 to about 50% by weight of the composition.
  • the binders or thickening agents according to the present invention are present in an amount of about 50% or less, 40% or less, e.g. 30% or less, 20% or less, 10% or less, 5%, or less.
  • Pharmaceutically acceptable lubricants for solid oral dosage forms as per present invention include stearic acid, zinc stearate, sucrose stearate, sodium benzoate, hydrogenated vegetable oil, calcium stearate, adipic acid, glyceryl palmitostearate, glyceryl monostearate, medium- chain triglycerides, glyceryl behenate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, magnesium stearate, polyethylene glycol.
  • the amount of lubricant according to the present invention ranges from 0 to about 20% by weight of the composition. In an embodiment, the lubricant according to the present invention is present in an amount of about 20% or less, e.g. 10% or less, 5% or less.
  • Various useful disintegrants and/or super-disintegrants for solid oral dosage forms as per present invention include, but are not limited to croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, povidone, crospovidone, polacriilin potassium, sodium starch glycolate, alginic acid, sodium alginate, calcium phosphate tribasic, colloidal silicon dioxide, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pre-gelatinized starch and/or combinations thereof.
  • the amount of disintegrant according to the present invention ranges from 0 to about 40% by weight of the composition. In an embodiment, the disintegrant according to the present invention is present in an amount of about 40% or less, 30% or less, e.g. 20% or less, 10% or less.
  • Suitable glidants for solid oral dosage forms as per present invention include, but are not limited to, calcium silicate, magnesium silicate, magnesium trisilicate, stearic acid and its derivatives or esters like magnesium stearate, calcium stearate, and sodium stearate and the corresponding esters such as sodium stearyl fumarate, talc, and colloidal silicon dioxide, tribasic calcium phosphate, starch or mixtures thereof.
  • the glidant according to the present invention is present in an amount of about 20% or less, e.g. 10% or less, 5% or less, 3% or less.
  • Suitable taste masking agents and/or flavoring agents and/or mouth-feel improvers include, but are not limited to, mint powder, menthol, vanillin, aspartame, acesulfame potassium, saccharin sodium, aromatics and/or natural oils, synthetic flavor oils, extracts from plants, leaves, flowers, fruits and combinations thereof, commercially available orange, grape, cherry, strawberry, and bubble gum flavors, tutti-frutti flavors, bitter taste masker flavors, commercially available bitter masker flavor, peppermint flavor, ion-exchange resins such as Amberlite, Amberlite ® CG 50, Amberlite ® IRP-64, Amberlite ® IRP-69, Indion ® 204, Indion ® 214, Indion ® 234, Indion ® CRP 244, Indion ® CRP 254, Carbomer 934, Carbomer 974, Carbomer 971, Carbopol ® 934P NF, Carbopol ® 97 IP, Carbopol ® 9
  • the amount according to the present invention ranges from 0 to about 40% by weight of the composition.
  • the taste masking agents and/or flavoring agents and/or mouth-feel improvers are present in an amount of about 0.01% to about 10% by weight of the composition.
  • sweetening agents or sweeteners include, but are not limited to, sugars such as sucrose, sucralose, glucose, dextrose, maltose, fructose, artificial sweeteners (such as saccharin, saccharin sodium, aspartame, acesulfame, acesulfame potassium, neohesperidine dihydrochalcone, mono-ammonium glycyrrhizinate, sugar alcohols (such as mannitol, xylitol, lactitol, maltitol syrup), thaumatin, monellin, dihydrochalcones, dipotassium glycyrrhizinate, stevia and mixtures thereof, present conveniently in an amount of from 0 to about 65% by weight of the composition.
  • the sweetening agent according to the present invention is present in an amount of about 0.01% to about 10% by weight of the composition.
  • Suitable pH adjusting substances or pH modifiers or buffering agents include, but are not limited to, hydrochloric acid, sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent potassium salt, alkaline oxide, citrate, phosphate, borate salts, carbonate salts, bicarbonate salts, basic amino acids, amino sugars.
  • the pH adjusting agents according to the present invention is present in an amount of about 10% or less, e.g. 5% or less, 3% or less.
  • Suitable antioxidants for use according to the invention include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate (AP), propyl gallate, sodium thiosulfate, alpha-tocopherol, D-alpha tocopherol, a-tocopherol acetate, D -a- Tocopherol polyethylene glycol 1000 succinate (TPGS) also known as vitamin E, thiourea, cysteine, sodium metabisulfite, dithiothreitol or any mixtures thereof.
  • the antioxidant is present in an amount of 0.0001% to 20% by weight, preferably 0.001% to 0.5% by weight, more preferably 0.01 to 0.2% by weight, even more preferably 0.05% by weight.
  • Solid carriers for solid oral dosage forms as per present invention include, but not limited to, magnesium trisilicate, magnesium hydroxide, talcum, crospovidone, cross-linked sodium carboxymethyl cellulose, and cross-linked polymethyl methacrylate, calcium silicate, amorphous silicon dioxide, hydrophilic fumed silica, silicon dioxide, colloidal silicon dioxide, hydrophobic colloidal silica, magnesium aluminometasilicate, magnesium stearate, starch, cellulose-based derivatives, microcrystalline cellulose, methylcellulose, HPMC, lactose, croscarmellose sodium, anhydrous dibasic calcium phosphate, calcium carbonate, carbon nanotubes, sodium-CMC, dextran, zinc dioxide, dextrin, maltodextrin, cyclodextrin, hp-b- CD, or mixtures thereof.
  • the amount of solid carrier according to the present invention ranges 5 from 0 to about 90% by weight of the composition.
  • compositions according to the present invention may further comprise other excipients such as lyoprotectants, cryoprotectants, plasticizers, and gelling agents.
  • excipients such as lyoprotectants, cryoprotectants, plasticizers, and gelling agents.
  • the amount of these excipients according to the present invention ranges from about 0% to about 90% by weight of the composition.
  • Remdesivir Lipid compositions were prepared by using quantitative formula as given in Table 1 to Table 4 (Quantity (%w/w)):
  • Dissolution The dissolution profile of the compositions prepared using quantitative composition, was measured in 900 ml of Mcllvaine Buffer (pH 3.0) using a USP II apparatus (Paddle) at a temperature of 37+0.5°C and a rotation speed of 50 revolutions per minute.
  • the quantitative composition as given below in Table 4 exhibited at least 75% of drug release in 15 minutes or less.

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Abstract

La présente invention concerne des compositions pharmaceutiques lipidiques comprenant du remdésivir ou ses sels ou solvate pharmaceutiquement acceptables. La présente invention concerne également un procédé de préparation de compositions lipidiques comprenant du remdésivir ou ses sels ou solvate pharmaceutiquement acceptables. Les compositions de remdésivir préparées selon la présente invention sont capables d'améliorer des attributs techniques pharmaceutiques tels qu'une capacité accrue de chargement en médicament, une dissolution, une stabilité et une biodisponibilité accrues. Les compositions de remdésivir préparées selon la présente invention sont utiles dans le traitement d'infections virales comprenant le coronavirus (COVID -19).
PCT/IN2021/050536 2020-06-03 2021-06-03 Compositions pharmaceutiques lipidiques de remdésivir Ceased WO2021245700A2 (fr)

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WO2024010441A1 (fr) * 2022-07-06 2024-01-11 Avantsar Sdn Bhd Formulation d'administration de médicament auto-émulsifiant présentant une biodisponibilité orale améliorée d'un composé lipophile

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WO2019018185A1 (fr) * 2017-07-15 2019-01-24 Arisan Therapeutics Inc. Dérivés énantiomériquement purs d'adamatane pour le traitement d'infections à filovirus
WO2020055368A2 (fr) * 2018-09-12 2020-03-19 Istanbul Medipol Universitesi Utilisation de molécules dérivées de coumarine terpénique dans le traitement de maladies virales
CN110960532A (zh) * 2020-02-21 2020-04-07 金晓飞 一种抗冠状病毒的博落回苄基异喹啉类生物碱与白藜芦醇组合物及其应用

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WO2024010441A1 (fr) * 2022-07-06 2024-01-11 Avantsar Sdn Bhd Formulation d'administration de médicament auto-émulsifiant présentant une biodisponibilité orale améliorée d'un composé lipophile
GB2622741A (en) * 2022-07-06 2024-03-27 Avantsar Sdn Bhd A self-emulsifying drug delivery formulation with improved oral bioavailability of lipophilic compound

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