The present invention relates to pharmaceutical lipid compositions of remdesivir or its pharmaceutically acceptable salts or solvates thereof. In particular, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, 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).
BACKGROUND OF THE INVENTION
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-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl] methoxy} (phenoxy)phosphoryl] amino} propanoate. Remdesivir is practically insoluble in water and is represented by the following formula as:

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.
The above-mentioned publications fail to disclose how to overcome the technical challenges associated with remdesivir for designing oral dosage forms. Further, published literature has also disclosed that remdesivir is not suitable for oral delivery. There are many factors that may impact oral bioavailability such as solubility profile of the drug, permeability, stability, and critical factors like dissolution and first-pass metabolism.
Development of pharmaceutical 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). 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.
However, the development of pharmaceutical compositions based on lipid drug delivery systems is challenging from a formulation development perspective. A number of technical parameters need to be considered like the selection of oil, surfactant, co-surfactant, the solubility of the drug in different oils, oil-surfactant pair, HLB value (hydrophilic-lipophilic balance), cosolvents and their concentrations, the temperature at which self-emulsification occur, and preparation of the phase diagram. Due to challenges associated with the development of lipid-based formulations, only a few formulations for oral delivery are marketed based on this technology. Examples of some marketed formulations are, e.g., cyclosporine, isotretinoin, and HIV drugs such as lopinavir or ritonavir.
Due to technical difficulties, 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. Further, the dose of remdesivir injection is 200 mg on day 1, followed by once-daily maintenance doses of 100 mg from day 2. Thus, administration of remdesivir injection in hospitalized patients is again a big challenge and accordingly requires trained and highly skilled medical professionals. Furthermore, 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.
In the pharmaceutical industry, there is a constant need to work on identifying and developing novel pharmaceutical compositions that certainly affect the drug's dissolution profile, bioavailability, bioequivalence, stability, etc. These all factors play important roles in achieving the desired therapeutic effect, and successful dosage form development with desired technical attributes. Therefore, in the case of remdesivir too, there is an unmet need to develop oral pharmaceutical compositions with desirable technical attributes such as solubility, dispersibility, dissolution, stability, bioavailability, and to facilitate patient compliance by self-administration by patients. The 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.
SUMMARY OF THE INVENTION
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.
DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.
As used herein, the term “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 lipid microparticles, solid lipid nanoparticles, nanostructure lipid carriers, lipid drug conjugates and the like. 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.
Throughout this specification and the claims, 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.
The term "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.
The term “self-emulsifying (SEDDS) drug delivery” as used herein 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).
The 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). As provided herein, 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. As provided herein, 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. The term "average” or “mean” particle/droplet size, as used herein, 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.
The term “stable” as used herein, 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. 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. In one embodiment of the invention, 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). In one embodiment, 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 µm, D50 is less than about 100 µm and D10 is less than about 50 µm. Preferably, particle size distribution is D90 is less than about 100 µm, D50 is less than about 70 µm and D10 is less than about 30 µm. 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, there is provided 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.
In another embodiment of the invention, the present invention provides a stable remdesivir composition in the form of an emulsion. In another embodiment of the composition that can be packed in larger bottles for many doses such as multi-dose bottles.
In another embodiment of the invention, there is provided 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.
In another embodiment of the invention, there is provided an oral liquid lipid pharmaceutical composition comprising: a) remdesivir, b) emulsifier, c) antioxidant, d) flavoring agent, and e) one or more pharmaceutically acceptable vehicles.
In another embodiment of the invention, there is provided 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. In another embodiment, the composition further comprises one or preservatives and sweetening agents.
In accordance with other embodiment of the present invention, there is provided 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. Preferably, 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.
In accordance with yet another embodiment of the present invention, there is provided 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.
In accordance with yet another embodiment of the present invention, there is provided 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. Particularly, the viscosity is in the range of 10 to 2500 cPs at 25°C. Particularly, 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).
In another embodiment of the invention, 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.
In another embodiment of the invention, 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. Preferably, the amount of remdesivir is in the range of about 5% to about 85% by weight of the composition. In one embodiment of the invention, 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.
In accordance with other embodiment of the present invention, there is provided 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.
In accordance with one aspect of the present embodiment, there is provided an oral lipid pharmaceutical composition comprising remdesivir and at least one or more pharmaceutically acceptable excipients, wherein the amount of remdesivir is 1mg/mL, 2mg/mL, 25mg/5mL, 50mg/5mL, 100mg/5mL, 200mg/5ml and 250mg/5mL, 5mg/mL, 25mg/mL, 20mg/ml, 50mg/mL, 100mg/mL and 250mg/mL. Particularly, the amount of remdesivir is 100mg/5mL.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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. In another embodiment, the composition is an oral liquid lipid composition.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, there is provided 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.
In another embodiment of the invention, there is provided 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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. In another embodiment of the invention, 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.
In another embodiment of the invention, 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. Optionally, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, there are provided oral lipid pharmaceutical compositions comprising remdesivir and at least one or more pharmaceutically acceptable excipients, wherein the composition is stable. In another embodiment, the composition is stable for at least one month while stored at 40°±2°C and 75±5% relative humidity.
In another embodiment of the invention, there is provided a composition, 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. In yet another embodiment, 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.
In another embodiment of the present invention, the oral lipid pharmaceutical compositions of the present invention are able to form in-situ homogeneous, thermodynamically stable, and uniform droplet sizes clear emulsion.
In another embodiment of the present invention, no phase separation of the oral lipid compositions has been observed under room conditions. In addition, 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.
In another embodiment, 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.
In another embodiment of the invention, there are provided oral lipid pharmaceutical compositions comprising remdesivir and at least one or more pharmaceutically acceptable excipients, wherein remdesivir has a particle size distribution D90 less than about 100 µm, D50 less than about 50 µm, and D10 less than about 20 µm.
In another embodiment of the invention, there are provided 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. In another embodiment, the composition has droplet size D90 from 1 micron to 100 microns. In another embodiment, the composition has droplet size D50 from 1 micron to 50 microns. In another embodiment, the composition has droplet size D10 from 1 micron to 20 microns. In another embodiment, the composition has droplet size D90 of about 20 microns, D50 of about 10 microns, and D10 of about 2 microns.
In particular, it has been found that oral lipid compositions of remdesivir surprisingly result in an increased dissolution rate. In another embodiment, the compositions exhibit at least 75% of the drug release in 15 minutes in 900 ml of McIlvaine 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.
In another embodiment, the pharmaceutical 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.
In another embodiment of the invention, there is provided 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 virus (MARV)), Flaviviridae, or Paramyxoviridae viral infections. In another embodiment, the present invention provides the use of pharmaceutical compositions in the treatment of coronavirus disease 2019 (COVID-19) infection.
In one embodiment, 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. In another embodiment, the composition is administered at least three times a day. In one embodiment, the compositions of the present invention can be given to diabetic patients because the composition is free of sugar.
In another embodiment, the pharmaceutical compositions as per the present invention are meant for pre-hospitalization use. In another embodiment, 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.
In certain embodiments, 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. In one embodiment, the compositions comprise a combination of remdesivir and baricitinib. In one embodiment, the oral liquid compositions comprise a combination of remdesivir and baricitinib.
Various useful 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 C8-C10), 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, or borage oil, tocopherols including tocopherol acetate, d-a-Tocopherol (vitamin E), D -a-Tocopherol polyethylene glycol 1000 succinate (TPGS) or combinations thereof. In some embodiments, 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). The term ‘oil’ according to the present invention 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. In an embodiment, 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 (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH40), polyoxyl 60 hydrogenated castor oil (Cremophor RH60), tocopherols including tocopherol acetate, d-a-Tocopherol (vitamin E), D -a-Tocopherol polyethylene glycol 1000 succinate (TPGS), propylene glycol esters of fatty acids, caprylic/capric, linoleaoyl macrogol glycerides (Labrafil®), PEG 300 oleic glycerides (Labrafil M-1944CS), PEG 300 linoleic glycerides (Labrafil M-2125CS), PEG caprylic/capric glycerides (Labrasol and its various grades), TRANSCUTOL®, TRANSCUTOL HP® (diethylene glycol monoethyl ether), phosphatidylcholine, Phosal 50PG® (50% phosphatidylcholine from soybean with propylenglycol, fluid), propylene glycol caprylate/caprate (Labrafac and its various grades), propylene glycol monolaurate (various grades of Lauroglycol), caprylocaproyl polyoxyl-8 glycerides, PEG 1500 lauric glycerides (Gelucire 44/14), glyceryl monooleate (Capmul GMO, Capmul-90 and other grades), glyceryl monostearate, macrogol 15 hydroxystearate (Solutol HS-15®), polyglyceryl oleate (Plurol oleique®), polyoxyethylene glycerol trioleate, and combinations thereof. The term “surfactant” according to the present invention 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. In an embodiment, 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, glycerol, polyethylene glycols chain lengths such as PEG and PEG 400), bile salts, sodium deoxycholate, ethyl oleate, poloxamer, tocopherols including tocopherol acetate, d-a-Tocopherol (vitamin E), D -a-Tocopherol polyethylene glycol 1000 succinate (TPGS), lecithin (phosphatidyl choline or lysophosphatidyl choline or like), phosphatidyl choline, propylene glycol, caprylate or a phosphatidic acid derivative thereof (such as propylene glycol monocaprylate) commercially available products like TRANSCUTOL®, TRANSCUTOL HP® (diethylene glycol monoethyl ether), phosphatidylcholine, Phosal 50PG® (50% phosphatidylcholine from soybean with propylenglycol, fluid), CAPRYOLTM (Propylene glycol monoca prylate-Type I), CAPRYOLTM 90 (propylene glycol monocaprylate-Type II), CAPMUL (glyceryl caprylate), TETRA GLYCOLTM (tetrahydrofurfuryl diethylene glycol ether), LABRAFIL® (Polyglycosylglycerides), LUTROL® F68 (polaxomer 188), CARBITOLTM (diethylene glycol monoethyl ether), dextran, maltodextrin, lactose, mannitol, arabic gum, glycine, glucose, dextran 40 or mixtures, propylene glycol esters of fatty acids, PEG 300 oleic glycerides (Labrafil M-1944CS), glyceryl monostearate, PEG 300 linoleic glycerides (Labrafil M-2125CS), PEG 400 caprylic/capric glycerides (Labrasol), propylene glycol caprylate/caprate (Labrafac and its various grades), propylene glycol monolaurate (Lauroglycol and its various grades), caprylocaproyl polyoxyl-8 glycerides, glyceryl monooleate (Capmul GMO, Capmul-90 and other grades), PEG 1500 lauric glycerides (Gelucire 44/14) and the like. The term ‘co-surfactant’ according to the present invention 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 esters, 1,3-trimethyl-2-imidazolidone, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, sorbitans, hexane glycol, hexanetriol propylene carbonate, triethyl citrate, tributyl citrate, triacetin, trichloroethylene, 1,1,1 – trichloroethane, toluene, perchloroethylene, 2-methoxyethanol (acetate), tetrahydrofuran, bases including organic bases, inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide, citrate, phosphate, borate salts, organic and inorganic acids such as citric acid, lactic acid, acetic acid, formic acid, oxalic acid, uric acid, malic acid, tartaric acid, succinic acid, benzoic acid, sorbic acid, ascorbic acid, phosphoric acid, boric acid, hydrochloric acid, 1 N hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid or hydrofluoric acid and combinations thereof. In an embodiment, the vehicles according to the present invention are 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 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. 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.
Various useful 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, polymethacrylates 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. In an embodiment, 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. In an embodiment, 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.
Various useful 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® 971P, Carbopol® 974P NF, Sentry® Polyox® WSR N80 NF and mixtures thereof. The amount according to the present invention ranges from 0 to about 40% by weight of the composition. In a preferred embodiment, 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.
Various useful 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. In a preferred embodiment, 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. In an embodiment, 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-ß-CD, or mixtures thereof. The amount of solid carrier according to the present invention ranges from 0 to about 90% by weight of the composition.
The compositions according to the present invention may further comprise other 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.
The following examples are provided to illustrate embodiments of the disclosure but they are by no means intended to limit its scope.
EXAMPLES (Ex.): Remdesivir Lipid compositions were prepared by using quantitative formula as given in Table 1 to Table 4 (Quantity (%w/w)):
Table 1
S. No. Ingredient Ex. 1 Ex. 2
1. Remdesivir 1-97 5-85
2. Baricitinib 0-80 -
3. Oil Phase 0-70 0.01-60
4. Surfactant 0-50 0.01-40
5. Co-Surfactant 0-50 0.01-40
6. Optional Other Excipients
7. Diluent 0-70 10-70
8. Binder 0-30 1-30
9. Disintegrant 0-20 1-20
10. Glidant 0-5 0.1-2
11. Lubricant 0-3 0.1-2
12. Solid Carrier 0-50 0.1-40
13. Buffering agent 0-10 0.1-5
14. Stabilizing agent 0-10 0.1-5
Table 2
S. No. Ingredients Ex. 3 Ex. 4 Ex. 5 Ex. 6
1. Remdesivir 10 30 60 90
2. Labrasol 15 20 15 -
3. Labrafac 20 15 - -
4. Lauroglycol-90 - 17.5 5 -
5. Capmul-90 45 - - -
6. D -a-Tocopherol polyethylene glycol 1000 succinate (TPGS) 5 10 10 2.5
7. Transcutol 2.5 5 7.5 5
8. Glyceryl monostearate 2.5 2.5 2.5 2.5
Table 3
S. No Ingredients Function Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11
1 Remdesivir API 0.01-20 10 10 5 5
2 Povidone Thickening agent 0-20 - 5 - 2.5
3 Cremophor Emulsifier 0-40 - 10 - 5
4 Corn Oil Mono-di-tri glycerides Oil/Emulsifier 0-30 5 - 2.5 -
5 D -a-Tocopherol polyethylene glycol 1000 succinate (TPGS) Antioxidant 0-30 16.8 - 8.4 -
6 Peppermint Flavour Flavouring agent 0-20 8.2 10 4.1 5
7 Glycerin Vehicle 0-30 - - - -
8 Propylene Glycol Vehicle 0-40 30 35 15 17.5
9 Polyethylene glycol Vehicle 0-40 30 30 15 15
10 Purified Water Vehicle q.s. q.s. q.s. q.s. q.s.
Procedure: 1) Thickening agent/Antioxidant was added to the suitable vehicle with stirring and heated at a suitable temperature to form a clear solution; 2) emulsifier and/or oil was added into the solution of step 1) and stirred to dissolve it completely; 3) suitable vehicles (such as glycerin and/or propylene glycol) were added into the solution of step 2) and stirred to dissolve it completely; 4) drug was added into the solution of step 3). the solution was heated at a suitable temperature to form a clear solution and stirred to dissolve it completely; 5) flavoring agent was added to the solution of step 4) and stirred to dissolve it completely.
Table 4
S. No. Ingredients Function Ex. 12 Ex. 13 Ex. 14
1 Remdesivir Active 0.01-20 2.0 2.0
2 Phosal 50 PG Surfactant 0-40 - 15.0
3 Transcutol Surfactant 0-40 - -
4 Labrasol Surfactant 0-40 - -
5 Cremophor RH 40 Surfactant 0-40 - -
6 Vitamin E TPGS Emulsifier 0-40 20.0 -
7 Thaumatin
(5% in Glycerine) Sweetener
(Vehicle) 0-20 10.0 10.0
8 Strawberry Flavoring agent 0-20 2.0 2.0
9 Methyl paraben Preservative 0-10 0.10 0.10
10 Propyl paraben Preservative 0-10 0.05 0.05
11 Propylene Glycol Vehicle 0-50 0.5 0.5
12 PEG 400 Vehicle 0-50 - 5.0
13 Water Vehicle q.s. q.s. q.s.
Procedure: 1) Preservative were added to the mixture of vehicles with stirring and heated at a suitable temperature to form a clear solution, 2) suitable emulsifier and/or vehicle was added to the solution of step 1), followed by heating at a suitable temperature to form a clear solution, 3) drug was added into the solution of step 2) followed by heating at a suitable temperature to form clear solution and stirred to dissolve completely, 4) sweetener was added in a suitable vehicle and stirred to dissolve followed by heating at a suitable temperature to form a clear solution, 5) The solution of step 4) was added with a suitable vehicle (water) and stirred for a suitable time, 6) suitable flavoring agent was added into the solution of step 5) and stirred to dissolve completely.
Results: Dissolution: The dissolution profile of the compositions prepared using quantitative composition, was measured in 900 ml of McIlvaine 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.
Table 5 - Percent Drug Release of Various Compositions
Time Point (min.) % Drug release
Ex. 8 Ex. 9
10 98 97
15 99 99
30 99 96
45 99 95
60 99 95

Table 6 - Assay (% w/w)
Assay (% w/w)
Ex. 8 Ex. 9 Ex. 14
96.8 99.1 101.1

WE CLAIM:
1. An oral lipid pharmaceutical 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.
2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition for oral administration is selected from the group consisting of powder, granules, pellets, beads, tablets, capsules, and liquid dosage form.
3. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition further comprises of one or more pharmaceutically acceptable excipients selected from a group consisting of diluent, binder, disintegrant, lubricant, solubilizer, glidant, surfactant, co-surfactant, oil phase, solid carrier, stabilizer, emulsifier, thickening agent, antioxidant, flavoring agent, sweetening agent, taste masking agent, and vehicle.
4. The pharmaceutical composition as claimed in claim 3, wherein the emulsifier is selected from the group consisting of polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene products of hydrogenated vegetable oils, polyethoxylated castor oils or polyethoxylated hydrogenated castor oil, polyoxyethylene castor oil derivatives, PEG caprylic/capric glycerides, propylene glycol caprylate/caprate, propylene glycol monolaurate, glyceryl monooleate, glyceryl monostearate, corn oil mono-di-tri glycerides, phosphatidylcholine, diethylene glycol monoethyl ether, D -a-Tocopherol polyethylene glycol 1000 succinate, or a combination thereof.
5. The pharmaceutical composition as claimed in claim 3, further comprises an oil phase selected from the group consisting of propylene glycol esters, long-chain fatty acids, edible oils, medium chain mono-, di-, or triglycerides, corn oil mono-di-tri glycerides, propylene glycol caprylate/caprate, propylene glycol monolaurate, glyceryl monooleate or a combination thereof.
6. The pharmaceutical composition as claimed in claim 1, wherein the remdesivir and emulsifier are used in the ratio of from 1:0.2 to 1:5.
7. An oral liquid lipid pharmaceutical composition comprising: a) remdesivir, b) emulsifier, c) antioxidant, d) flavoring agent and e) one or more pharmaceutically acceptable vehicles.
8. The pharmaceutical composition as claimed in claim 7, wherein the amount of remdesivir is from about 0.1 mg/mL to about 200 mg/mL.
9. The oral liquid lipid pharmaceutical composition as claimed in claim 7, further comprising: a) remdesivir in an amount of about 1% to about 85% by weight, b) emulsifier in an amount of 0.01% to about 30% by weight, c) antioxidant in an amount of about 0.01% to about 30% by weight, d) flavoring agent in an amount of about 0.01% to about 20% by weight, e) one or more vehicles in an amount of about 0.001% to about 90% by weight and optionally one or more pharmaceutically acceptable excipients.
10. The liquid composition as claimed in claim 7, wherein the composition releases at least 75% of the drug in 15 minutes in 900 ml of McIlvaine 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.