WO2023118928A1 - Stable nanoformulation for lipophilic actives, oral dosage form and process for its preparation - Google Patents

Stable nanoformulation for lipophilic actives, oral dosage form and process for its preparation Download PDF

Info

Publication number
WO2023118928A1
WO2023118928A1 PCT/IB2021/062069 IB2021062069W WO2023118928A1 WO 2023118928 A1 WO2023118928 A1 WO 2023118928A1 IB 2021062069 W IB2021062069 W IB 2021062069W WO 2023118928 A1 WO2023118928 A1 WO 2023118928A1
Authority
WO
WIPO (PCT)
Prior art keywords
nanoformulation
stable
external phase
dosage form
oral dosage
Prior art date
Application number
PCT/IB2021/062069
Other languages
French (fr)
Inventor
Praveen Khullar
Sameer KATIYAR
Rasvita GAWAS
Vaibhav MEHROTRA
Surabhi GAONKAR
Amit BADERIYA
Satish Kumar BEDADA
Sagar ADICHWAL
Santosh Kumar Deolia
Shrikrishna PAWAR
Kiran AGARADAHALLI
Original Assignee
Opella Healthcare Group Sas
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Opella Healthcare Group Sas filed Critical Opella Healthcare Group Sas
Priority to PCT/IB2021/062069 priority Critical patent/WO2023118928A1/en
Publication of WO2023118928A1 publication Critical patent/WO2023118928A1/en

Links

Classifications

    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the present invention relates to a nanoemulsion for delivery of lipophilic actives with improved physical and/or chemical stability, which is useful as or for the preparation of oral dosage forms with improved bioavailability.
  • the nanoemulsion of the invention comprises a lipophilic active, such as cholecalciferol, at least two nonionic surfactants, pharmaceutically acceptable excipients and water, and its improved stability is independent of external phase viscosity.
  • a process for its preparation is also disclosed and involves increasing the surface charge of the nanoformulation.
  • Nanoemulsions are biphasic dispersion of two immiscible liquids, wherein small droplets of one immiscible liquid is in another immiscible liquid to form a single phase by means of an emulsifying agent (i.e. surfactant and co-surfactant).
  • an emulsifying agent i.e. surfactant and co-surfactant.
  • nanoemulsions are either oil-in-water (O/W) or water-in-oil (W/O) type.
  • Nanoemulsions serve as vehicles for the delivery of active pharmaceutical ingredients as well as other bioactives. They are designed to address some of the problems associated with conventional drug delivery systems such as low bioavailability.
  • the bioavailability of encapsulated non-polar components is higher in nanoemulsions than conventional emulsions.
  • the small particle size and high surface- to-volume ratio can contribute with a higher bioavailability (Acosta, 2009; Huang, Yu, & Ru, 2010).
  • Nanoemulsions may be therefore particularly useful for increasing the bioactivity of lipophilic components that are normally poorly absorbed.
  • a previous report shows that a nanosystem technology used as oral delivery route has succeed in stabilizing the nanosystem by increasing the viscosity of external medium, via hydrogen bonding (Qian et al., 2011).
  • WO2015155703 discloses a stable nanodispersion comprising an aqueous dispersion medium, a dispersed phase, a surface active agent and optionally, an additive, wherein the aqueous dispersion medium comprises a nanodispersion stabilizing vehicle base component (NSVBC).
  • NSVBC nanodispersion stabilizing vehicle base component
  • Said NSVBC improves long term physical stability (e. . up to one year) of the nanodispersion with or without particle size reduction
  • said dispersed phase comprises a lipophilic/hydrophobic bioactive compound.
  • RSC Adv., 2017,7,19815-19827 discloses that the nonionic surfactants Cremophor and Tween are frequently used (but not within the same composition) for the development of pharmaceutical emulsions but teaches that stabilization of the low-level Cremophor EL O/W nanoemulsion is achieved by adding short-chain alcohols and other cosurfactants.
  • the present invention provides a nanoemulsion with improved stability independent of external phase viscosity and without the requiring the use of nanodispersion stabilizing vehicle base components (NSVBC). Summary of the Invention
  • the objective technical problem to be solved by the present invention is to provide an alternative stable nanoformulation for delivery of lipophilic actives.
  • the present invention provides a nanoformulation with good stability, which is independent of external phase viscosity, and without the need for any nanodispersion vehicle imparting viscosity to external phase (hereafter denoted as NVVEP).
  • the nanoformulation of the present invention has increased surface charge of the system and is stable even when the zeta potential is between lOmV and -lOmV.
  • the present invention provides a stable nanoformulation comprising a lipophilic active, at least two nonionic surfactants, optional pharmaceutically acceptable excipients, and water.
  • the present invention provides a stable nanoformulation as an oral dosage form.
  • the present invention provides an oral dosage form of lipophilic actives comprising a nanoformulation which is useful for improved bioavailability and/or bioactivity and said lipophilic active.
  • the nanoformulation of the invention is useful for delivery of lipophilic actives.
  • the stable nanoformulation of the invention comprises a lipophilic active, at least two nonionic surfactants, optional pharmaceutically acceptable excipients, and water.
  • nanoparticles is used in the context of the nanoemulsion, that is, said nanoparticles are in the liquid state and are the structures which contain the lipophilic actives/drug.
  • the stable nanoformulation is a stabilized nanosystem, with or without surface charge stabilization, which is surprisingly not dependent on external phase viscosity for physical stabilization.
  • the formulation of the invention comprises a lipophilic active/drug within nanoparticles and an external phase comprising at least on nonionic surfactant.
  • the present invention also provides at least other two technical features:
  • the surface charge as indicated by Zeta potential, has been increased for stabilizing the nanosystem. This helps in physical separation and reduced interaction of the individual nanosystem with one another, reducing chances of aggregation and agglomeration.
  • the invention thus provides increased physical stability of the system and is not dependent on the viscosity of external phase medium; and/or
  • the formulation of the invention is surprisingly stable.
  • This zone is considered as an unstable zone since the low zeta potential is not sufficient for stabilization (as explained in point 1).
  • the physical stability is surprisingly intact in the present nanoformulation, which leads to the enhanced stability of the formulation even in absence of the surface charge stabilization.
  • the behavior has been shown to be viscosity independent (viscosity stabilization is known in prior art).
  • viscosity stabilization is known in prior art.
  • a stable nanoformulation comprising: nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants; an external phase comprising at least one nonionic surfactant; optionally pharmaceutically acceptable excipients; and water.
  • a nanoformulation as described above comprising: 0.002- 0.2%, alternatively 0.001-0.2%, alternatively 0.05-0.2%, alternatively 0.001% of a lipophilic active/drug; 0.04-0.6%, alternatively 0.05-0.6%, alternatively 0.1-0.5%, alternatively 0.05-0.5% of Cremophor RH40; 0.04-0.8%, alternatively 0.02%-0.8%, alternatively 0.01%-0.8%, alternatively 0.1-0.8& of polysorbate 80; and 0.0002-0.1%, alternatively 0.0005-0.1%, alternatively 0.001-0.1%, alternatively 0.005-0.1%, alternatively 0.05-0.1%, alternatively 0.01-0.1% of BHT, and water.
  • a nanoformulation as described above as an oral dosage form of cholecalciferol is described above as an oral dosage form of cholecalciferol.
  • An oral dosage form of lipophilic actives comprising: nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants; an external phase comprising at least one nonionic surfactant; optionally pharmaceutically acceptable excipients in the nanoparticles and/or in the external phase; and water.
  • An oral dosage form of cholecalciferol comprising: nanoparticles comprising cholecalciferol, cremophor RH40, polysorbate80, and BHT; an external phase comprising polysorbate 80; and water, wherein the concentration of ingredients in the oral dosage form is 0.002-0.2% of cholecalciferol; 0.04-0.6% of cremophor RH40; 0.04-0.8% of polysorbate 80; and 0.0002-0.1% of BHT, optionally further comprising other excipients in the external phase as described herein.
  • An oral dosage form of a lipophilic active/drug comprising: nanoparticles comprising cholecalciferol, cremophor RH40, polysorbate80, and BHT; an external phase comprising polysorbate 80; and water, wherein the concentration of ingredients in the oral dosage form is 0.002-0.2%, alternatively 0.001-0.2%, alternatively 0.05-0.2%, alternatively 0.001% of a lipophilic active/drug (e.g.
  • cholecalciferol, clobazam, and/or ramipril 0.04-0.6%, alternatively 0.05-0.6%, alternatively 0.1-0.5%, alternatively 0.05-0.5% of Cremophor RH40; 0.04- 0.8%, alternatively 0.02%-0.8%, alternatively 0.01%-0.8%, alternatively 0.1-0.8& of polysorbate 80; and 0.0002-0.1%, alternatively 0.0005-0.1%, alternatively 0.001-0.1%, alternatively 0.005-0.1%, alternatively 0.05-0.1%, alternatively 0.01-0.1% of BHT, , optionally further comprising other excipients in the external phase as described herein.
  • a process for the preparation of a stable nanoformulation comprising the steps of: a) preparing a nano-preconcentrate by adding a lipophilic active into at least a first nonionic surfactant and a first quantity of a second nonionic surfactant, mixing and solubilizing the active and optionally adding an excipient into the above mixture under stirring; b) preparing an external phase solution with at least a second quantity of said second nonionic surfactant, optionally further adding a third surfactant and/or an aqueous solution with other ingredients/excipients and homogenizing; c) adding said preconcentrate into said external phase solution under stirring and optionally adding aqueous solution with other ingredients/excipients and homogenizing, then allowing primary stabilization of this mixture under stirring; and d) adding water to make up the volume and secondary stabilization of final formulation under stirring.
  • the nonionic surfactants are selected from the group comprising PEG-40 Hydrogenated Castor Oil (Cremophor® RH40), Polysorbate 80, Polyoxyl castor oil, Ethoxylated sorbitan esters (Polysorbate 80, Polysorbate 20 and Polysorbate 60), polyethylene Glycol derivatives, Span series, Brij series of surfactants.
  • the nonionic surfactants are selected from the group comprising PEG-40 Hydrogenated Castor Oil, Polysorbate 20, Span 20, Polysorbate 80, Polyoxyl castor oil, Polysorbate 60, and combinations thereof.
  • the surfactant may be present in the composition in an amount in the range from about 0.01% w/v to about 1.5% w/v.
  • the nonionic surfactants are cremophor and polysorbate.
  • the ratio of Cremophor to Polysorbate can range from about 20:80 to about 80:20.
  • the pharmaceutically acceptable excipients are selected from the group comprising: sweeteners, flavoring agents, preservatives, antioxidants, pH modifiers, coloring agents, and combinations thereof.
  • sweeteners which can be used in the present invention are selected from, but are not limited to, the group comprising: sucralose, maltitol, lactose anhydrous and sucrose.
  • the sweetener is present in the nanoemulsion in an amount in the range from about 0.050 to 67% w/v, preferably 0.066 to 0.6%, more preferably less than 1% w/v.
  • Flavoring agents suitable to be used in the present invention can be selected from, but are not limited to, the group comprising: Pineapple flavor RSV, citrus flavor family, preferably, pineapple, pineapple mango, Ginger pineapple, Pineapple orange, Pineapple grapefruit, Fresh cut pineapple, and combinations thereof.
  • the flavoring agents are present in the nanoemulsion in an amount selected from the range of 0.0013 to 0.2% w/v.
  • Some preservatives suitable to be used in the present nanoformulation can be selected from, but are not limited to, the group comprising: Potassium Sorbate, class of sorbates, benzoates, parabens, benzyl alcohol, cresols, phenols, Quaternary ammoniums, and combinations thereof.
  • the preservatives are present in the nanoemulsion in an amount selected from the range of about 0.02 to 1.0% w/v.
  • Suitable antioxidants to be used in the present invention can be selected from, but are not limited to, the group comprising: Disodium EDTA, BHT, Disodium EDTA, BHT, Tocopherol Acetate, TPGS (with linker of 1000 and 2000), Ascorbic acid, Sodium Metabisulphite, BHA, and combinations thereof.
  • the antioxidants are present in the nanoemulsion in an amount in the range of about 0.00002 to 0.5% w/v.
  • coloring agents can be select from, but are not limited to, the group comprising: tartrazine yellow, FD&C Yellow No. 5, FD&C Yellow No. 6, FD&C Yellow No. 10.
  • the coloring agents are present in the nanoemulsion in an amount in the range of about 0.0001 to 0. l%w/v.
  • an anionic surfactant is optionally added to the nanoformulation.
  • Suitable anionic surfactants to be added can be selected from the group comprising: SDS (sodium dodecyl sulfate), SLES (sodium laureth sulfate) and Docusate, wherein the anionic surfactants are present in the nanoemulsion in an amount in the range of about 0.003 to 0.8% w/v.% w/v, alternatively about 0.005 to 0.8% w/v.% w/v, alternatively about 0.01 to 0.8% w/v.% w/v, alternatively 0.005 to 0.7% w/v.% w/v.
  • the nanoformulation is an oral dosage form.
  • the invention provides an oral dosage form of lipophilic actives comprising:
  • nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants
  • the process for the preparation of a stable nanoformulation comprises the steps of: a) addition of a lipophilic active into at least a first nonionic surfactant and a second nonionic surfactant; b) mixture and solubilizing the active; c) addition of an antioxidant into the above mixture under stirring, thus forming a nano- preconcentrate; d) addition of said preconcentrate into a second quantity of said second nonionic surfactant under stirring (external phase solution); e) primary stabilization of external phase mixture under stirring; f) sequential addition of aqueous solution of other ingredients/excipients to said final external phase; and g) final addition of water to make up the volume and secondary stabilization of final formulation under stirring.
  • the process comprises the steps of: a) addition of a lipophilic active into a first nonionic surfactant and a second nonionic surfactant, this second surfactant being present at 70-80% of its total concentration in the final formulation; b) mixture and solubilizing the active/drug at 30-45°C; c) addition of an antioxidant into the above mixture under stirring, thus forming a nano-preconcentrate; d) addition of the preconcentrate to an external phase comprising a second quantity of said second nonionic surfactant (remaining 20-30%), under continuous stirring and maintaining the temperature at 30-50°C during addition of the preconcentrate; e) primary stabilization of external phase mixture under stirring for time period up to 8 hours; f) sequential addition of aqueous solution of all other ingredients/excipients to final external phase; and g) final addition of water to make up the volume (q.s.) and secondary stabilization of final formulation under stirring for time period up to 8 hours.
  • the second non-ionic surfactant is added in external phase based on HLB value (hydrophilic lipophilic balance, or the size and strength of the hydrophilic and lipophilic moi eties of a surfactant molecule).
  • HLB value hydrophilic lipophilic balance, or the size and strength of the hydrophilic and lipophilic moi eties of a surfactant molecule.
  • HLB hydrophilic lipophilic balance, or the size and strength of the hydrophilic and lipophilic moi eties of a surfactant molecule.
  • HLB value hydrophilic lipophilic balance, or the size and strength of the hydrophilic and lipophilic moi eties of a surfactant molecule.
  • the duration of said stirring ranges for primary stabilization up to 8 hours and secondary stabilization from up to 8 hours.
  • the stirring is a center vortex stirring.
  • the speed of stirring can range from about 200 RPM to about 1000 RPM.
  • NWEP component (Strength 60000IU/5ml & 7000 IU/5ml)
  • Formula 2 Surface Charge Stabilized (SCS) Nanosystem without NVVEP component (Strength 60000IU/5ml & 7000 IU/5ml)
  • Example 4 Physical stability and particle size
  • Example 5 Oral dosage form of cholecalciferol
  • This embodiment provides an oral dosage form of cholecalciferol as described in example 4, comprising: nanoparticles comprising cholecalciferol, cremophor RH 40, polysorbate 80 and BHT; an external phase comprising polysorbate 80 and other excipients; and water.
  • the effectiveness of the present invention was also shown with other lipophilic actives besides cholecalciferol.
  • the present example uses clobazam and ramipril (two different categories of drugs) to evaluate their potential and applicability in the nanoformulation of the present invention.
  • the results show that the nanoformulation of the invention is also functional and useful for other lipophilic actives/molecules. In one embodiment, this is feasible with the same concentrations and excipients that were also tested for cholecalciferol.
  • Embodiment 1 A stable nanoformulation comprising: nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants; an external phase comprising at least one nonionic surfactant; optionally pharmaceutically acceptable excipients in the nanoparticles and/or in the external phase; and water.
  • the lipophilic active ingredient may be cholecaliferol, clobazam, or ramipril.
  • Embodiment 2 The stable nanoformulation according to embodiment 1, wherein no phase viscosity stabilizer is used in the external phase.
  • Embodiments The stable nanoformulation according to embodiment 1 or 2, wherein the nanoparticle range in size less than 500 nm.
  • Embodiment 4 The stable nanoformulation according to embodiment 1, 2 or 3, wherein the zeta potential is between lOmV and -lOmV.
  • Embodiment 5 The stable nanoformulation according to any one of embodiments 1-4, wherein the lipophilic active is selected from the group comprising: D vitamins, benzodiazepines and angiotensin converting enzyme inhibitor, cholecalciferol, clobazam, Ramipril, or combinations thereof.
  • the lipophilic active is selected from the group comprising: D vitamins, benzodiazepines and angiotensin converting enzyme inhibitor, cholecalciferol, clobazam, Ramipril, or combinations thereof.
  • Embodiment 6 The stable nanoformulation according any one of embodiments 1-5, wherein the nonionic surfactants are selected from PEG-40 Hydrogenated Castor Oil, Polysorbate 80, Polyoxyl castor oil, Ethoxylated sorbitan esters, polyethylene Glycol derivatives, Span series, Brij series of surfactants or combinations thereof.
  • the nonionic surfactants are selected from PEG-40 Hydrogenated Castor Oil, Polysorbate 80, Polyoxyl castor oil, Ethoxylated sorbitan esters, polyethylene Glycol derivatives, Span series, Brij series of surfactants or combinations thereof.
  • Embodiment 7 The stable nanoformulation according to any one of embodiments 1-6, wherein the nonionic surfactants are in the range of from 0.01% w/v to 1.5% w/v.
  • Embodiment 8 The stable nanoformulation according to any one of embodiments 1-7, wherein the pharmaceutically acceptable excipients are selected from the group comprising: sweetener, flavoring agent, preservative, antioxidant, pH modifiers, coloring agents, or combinations thereof.
  • Embodiment 9 The stable nanoformulation according to any one of embodiments 1-8 further comprising an anionic surfactant.
  • Embodiment 10 The stable nanoformulation according to embodiment 9, wherein the anionic surfactant is selected from the group comprising: sodium dodecyl sulfate, sodium laureth sulfate and docusate, and combinations thereof.
  • the anionic surfactant is selected from the group comprising: sodium dodecyl sulfate, sodium laureth sulfate and docusate, and combinations thereof.
  • Embodiment 11 The stable nanoformulation according to any one of embodiments 1-10, comprising: 0.002-0.2% of a lipophilic active/drug; 0.04-0.6% of cremophor RH40; 0.04-0.8% of polysorbate 80; and 0.0002-0.1% ofBHT, and water.
  • Embodiment 12 The stable nanoformulation according to embodiment 11, further comprising: 0.2-0.6% sucralose; 20-40% of maltitol; 1-4% of anhydrous lactose; 0.1-0.3% of potassium sorbate; 0.04-0.2% of disodium EDTA; 0.01-0.04% of citric acid monohydrate; 0.002-0.001% of tartrazine yellow; and 0.04-0.2% of pineapple flavor RSV
  • Embodiment 13 The stable nanoformulation according to embodiment 11, further comprising: 33.33-66.55% of sucrose; 0.066-0.266% of potassium sorbate; 0.013-0.066% of disodium EDTA; 0.003-0.013% of citric acid monohydrate; 0.013- 0.1% of pineapple flavor RSV.
  • Embodiment 14 The stable nanoformulation according to any one of embodiments 1-13 as an oral dosage form of cholecalciferol.
  • Embodiment 15 The stable nanoformulation according to any one of embodiments 1-13 as an oral dosage form of clobazam or ramipril.
  • Embodiment 16 The stable nanoformulation according to any one of embodiments 1-15, wherein the nanoformulation does not comprise a nondispersion vehicle imparting viscosity to an external phase.
  • Embodiment 17 An oral dosage form of lipophilic actives comprising: nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants; an external phase comprising at least one nonionic surfactant; optionally pharmaceutically acceptable excipients in the nanoparticles and/or in the external phase; and water.
  • Embodiment 18 The oral dosage form according to embodiment 17 wherein the lipophilic active is cholecalciferol.
  • Embodiment 19 The oral dosage form according to embodiment 17 wherein the lipophilic active is clobazam and/or ramipril.
  • Embodiment 20 Oral dosage form of cholecalciferol comprising: nanoparticles comprising cholecalciferol, cremophor RH40, polysorbate80, and BHT; an external phase comprising polysorbate 80; and water, wherein the concentration of ingredients in the oral dosage form is 0.002-0.2% of cholecalciferol; 0.04-0.6% of cremophor RH40; 0.04-0.8% of polysorbate 80; and0.0002-0.1% of BHT.
  • Embodiment 21 The oral dosage form of any one of embodiments 17-20, wherein the dosage form does not comprise a nondispersion vehicle imparting viscosity to an external phase.
  • Embodiment 22 A process for the preparation of a stable nanoformulation comprising the steps of: a) preparing a nano-preconcentrate by adding a lipophilic active into at least a first nonionic surfactant and a first quantity of a second nonionic surfactant, mixing and solubilizing the active and optionally adding an excipient into the above mixture under stirring; b) preparing an external phase solution with at least a second quantity of said second nonionic surfactant, optionally further adding a third surfactant and/or an aqueous solution with other ingredients/excipients and homogenizing; c) adding said preconcentrate into said external phase solution under stirring and optionally adding aqueous solution with other ingredients/excipients and homogenizing, then allowing primary stabilization of this mixture under stirring; and d) adding water to make up the volume and secondary stabilization of final formulation under stirring.
  • Embodiment 23 A process according embodiment 22 wherein:
  • said second nonionic surfactant is added in the preconcentrate at 70-80% of its total quantity in the final formulation;
  • the step of mixture and solubilizing the active is performed at 30-45°C;
  • the secondary stabilization of final formulation under stirring is made for up to 8 hours.
  • the process includes each of these steps. Alternatively, the process includes one, two, three, or four of these steps.
  • Embodiment 24 A process according embodiment 22 comprising the steps of:
  • nano-preconcentrate into external phase solution of polysorbate (remaining 20-30% of its total quantity) under continuous stirring and temperature maintained at 30-50°C during addition of the nano-preconcentrate;

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a nanoemulsion for delivery of lipophilic actives with improved physical and/or chemical stability, which is useful as or for the preparation of oral dosage forms with improved bioavailability. The nanoemulsion of the invention comprises a lipophilic active, such as cholecalciferol, at least two nonionic surfactants, pharmaceutically acceptable excipients and water, and its improved stability is independent of external phase viscosity. A process for its preparation is also disclosed and involves increasing the surface charge of the nanoformulation.

Description

STABLE NANOFORMULATION FOR LIPOPHILIC ACTIVES, ORAL DOSAGE
FORM AND PROCESS FOR ITS PREPARATION
Field of the Invention
[0001] The present invention relates to a nanoemulsion for delivery of lipophilic actives with improved physical and/or chemical stability, which is useful as or for the preparation of oral dosage forms with improved bioavailability. The nanoemulsion of the invention comprises a lipophilic active, such as cholecalciferol, at least two nonionic surfactants, pharmaceutically acceptable excipients and water, and its improved stability is independent of external phase viscosity. A process for its preparation is also disclosed and involves increasing the surface charge of the nanoformulation.
Background of the Invention
[0002] It is of general knowledge in the art that some active pharmaceutical ingredients, particularly lipophilic active ingredients pose difficulties in bioavailability and/or to preparation procedures. Their vulnerability to chemical transformation during processing, storage, or digestion may also limit their bioavailability and bioactivity. Colloidal systems as nanoemulsions are being specifically designed to increase the water-dispersibility, chemical stability, and bioavailability of lipophilic functional ingredients.
[0003] Nanoemulsions are biphasic dispersion of two immiscible liquids, wherein small droplets of one immiscible liquid is in another immiscible liquid to form a single phase by means of an emulsifying agent (i.e. surfactant and co-surfactant). Typically, nanoemulsions are either oil-in-water (O/W) or water-in-oil (W/O) type.
[0004] Nanoemulsions serve as vehicles for the delivery of active pharmaceutical ingredients as well as other bioactives. They are designed to address some of the problems associated with conventional drug delivery systems such as low bioavailability.
[0005] The bioavailability of encapsulated non-polar components is higher in nanoemulsions than conventional emulsions. The small particle size and high surface- to-volume ratio can contribute with a higher bioavailability (Acosta, 2009; Huang, Yu, & Ru, 2010). Nanoemulsions may be therefore particularly useful for increasing the bioactivity of lipophilic components that are normally poorly absorbed.
[0006] A previous report shows that a nanosystem technology used as oral delivery route has succeed in stabilizing the nanosystem by increasing the viscosity of external medium, via hydrogen bonding (Qian et al., 2011).
[0007] WO2015155703 discloses a stable nanodispersion comprising an aqueous dispersion medium, a dispersed phase, a surface active agent and optionally, an additive, wherein the aqueous dispersion medium comprises a nanodispersion stabilizing vehicle base component (NSVBC). Said NSVBC improves long term physical stability (e. . up to one year) of the nanodispersion with or without particle size reduction, and said dispersed phase comprises a lipophilic/hydrophobic bioactive compound. Notwithstanding, said document neither anticipates nor suggests the teachings of the present invention. The present invention differs from said document for multiple reasons, including the fact that the nanodispersion product of the invention is stabilized by other means and does not required the use of NSVBCs.
[0008] Carpenter et al. "'Formation and surface -stabilizing contributions to bare nanoemulsions created with negligible surface charge”,' PNAS,' May 7, 2019; vol. 116; no. 19; pages 9214-9219 discloses that nanoemulsions in the absence of emulsifiers have been observed to acquire a significant negative charge at their surface, which ultimately contributes to their stability. Carpenter et al. also discloses that the process of creating low-charge nanoemulsions (LCNEs) required rigorous cleaning procedures and proper solvent storage conditions. These drawbacks are solved by the present invention.
[0009] Zeng L. ‘‘Development and characterization of promising Cremophor EL- stabilized o/w nanoemulsions containing short-chain alcohols as a cosurfactant” RSC Adv., 2017,7,19815-19827 discloses that the nonionic surfactants Cremophor and Tween are frequently used (but not within the same composition) for the development of pharmaceutical emulsions but teaches that stabilization of the low-level Cremophor EL O/W nanoemulsion is achieved by adding short-chain alcohols and other cosurfactants.
[0010] However, there remains a need for alternative nanoformulations with improved physical stability. The present invention provides a nanoemulsion with improved stability independent of external phase viscosity and without the requiring the use of nanodispersion stabilizing vehicle base components (NSVBC). Summary of the Invention
[0011] The objective technical problem to be solved by the present invention is to provide an alternative stable nanoformulation for delivery of lipophilic actives.
[0012] The present invention provides a nanoformulation with good stability, which is independent of external phase viscosity, and without the need for any nanodispersion vehicle imparting viscosity to external phase (hereafter denoted as NVVEP).
[0013] The nanoformulation of the present invention has increased surface charge of the system and is stable even when the zeta potential is between lOmV and -lOmV.
[0014] In one aspect, the present invention provides a stable nanoformulation comprising a lipophilic active, at least two nonionic surfactants, optional pharmaceutically acceptable excipients, and water.
[0015] In another aspect, the present invention provides a stable nanoformulation as an oral dosage form.
[0016] In another aspect, the present invention provides an oral dosage form of lipophilic actives comprising a nanoformulation which is useful for improved bioavailability and/or bioactivity and said lipophilic active.
[0017] In another aspect, there is provided a process for the preparation of a stable nanoformulation.
[0018] These and other objects of the invention will be more readily appreciated in the hereinbelow detailed description.
Detailed Description of the Invention
[0019] The nanoformulation of the invention is useful for delivery of lipophilic actives. The stable nanoformulation of the invention comprises a lipophilic active, at least two nonionic surfactants, optional pharmaceutically acceptable excipients, and water.
[0020] In the present invention, the terms “nanoformulation”, “nanosystem”, “nanoemulsion” and “nanodispersion” are used interchangeably herein, unless stated otherwise. In the present invention the term “nanoparticles” is used in the context of the nanoemulsion, that is, said nanoparticles are in the liquid state and are the structures which contain the lipophilic actives/drug.
[0021] Except for the numbers in the examples or where stated otherwise, all the numbers in this description indicate an amount of ingredient or condition of reaction are to be understood as modified by the word “about.” Percentages are to be understood as %w/v unless stated otherwise.
[0022] As used herein, the term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of between ± 20% and ± 0.1%, preferably ± 20% or ± 10%, more preferably ± 5%, even more preferably ± 1%, and still more preferably ± 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
[0023] Before certain embodiments are described in greater detail, it is to be understood that this invention is not limited to certain embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing certain embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[0024] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
[0025] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods, and materials are now described.
[0026] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.
[0027] It is noted that, as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative" limitation.
[0028] Each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.
[0029] In one embodiment, the stable nanoformulation is a stabilized nanosystem, with or without surface charge stabilization, which is surprisingly not dependent on external phase viscosity for physical stabilization. The formulation of the invention comprises a lipophilic active/drug within nanoparticles and an external phase comprising at least on nonionic surfactant.
[0030] The present invention also provides at least other two technical features:
1) The surface charge, as indicated by Zeta potential, has been increased for stabilizing the nanosystem. This helps in physical separation and reduced interaction of the individual nanosystem with one another, reducing chances of aggregation and agglomeration. The invention thus provides increased physical stability of the system and is not dependent on the viscosity of external phase medium; and/or
2) Even when the zeta potential is between lOmV and -lOmV, which theoretically would be considered as unstable, the formulation of the invention is surprisingly stable. This zone is considered as an unstable zone since the low zeta potential is not sufficient for stabilization (as explained in point 1). However, the physical stability is surprisingly intact in the present nanoformulation, which leads to the enhanced stability of the formulation even in absence of the surface charge stabilization. On the other hand, as matter of the fact, the behavior has been shown to be viscosity independent (viscosity stabilization is known in prior art). This is yet another unique and surprising feature of the invention. Thus, the present invention provides a nanoformulation as a stabilized nanosystem (with or without surface charge stabilization) which is surprisingly not dependent on external phase viscosity for physical stabilization and the system is stable both physically and chemically.
[0031] Further embodiments of the disclosure are shown below.
[0032] A stable nanoformulation comprising: nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants; an external phase comprising at least one nonionic surfactant; optionally pharmaceutically acceptable excipients; and water.
[0033] A nanoformulation as described above, wherein no phase viscosity stabilizer is used in the external phase.
[0034] A nanoformulation as described above, wherein the nanoparticles' size ranges less than 500 nm, alternatively less than 450 nm, alternatively less than 400 nm, alternatively less than 350 nm, alternatively less than 300 nm, alternatively less than 250 nm, alternatively less than 200 nm.
[0035] A nanoformulation as described above, wherein the zeta potential is between lOmV and -lOmV.
[0036] A nanoformulation as described above, wherein the lipophilic active is selected from the group comprising: D vitamins, benzodiazepines and angiotensin converting enzyme inhibitor, cholecalciferol, clobazam, Ramipril, or combinations thereof.
[0037] A nanoformulation as described above, comprising: 0.002-0.2% of a lipophilic active/drug; 0 04-0.6% of Cremophor RH40; 0.04-0.8% of polysorbate 80; and 0.0002- 0.1% of BHT, and water. A nanoformulation as described above, comprising: 0.002- 0.2%, alternatively 0.001-0.2%, alternatively 0.05-0.2%, alternatively 0.001% of a lipophilic active/drug; 0.04-0.6%, alternatively 0.05-0.6%, alternatively 0.1-0.5%, alternatively 0.05-0.5% of Cremophor RH40; 0.04-0.8%, alternatively 0.02%-0.8%, alternatively 0.01%-0.8%, alternatively 0.1-0.8& of polysorbate 80; and 0.0002-0.1%, alternatively 0.0005-0.1%, alternatively 0.001-0.1%, alternatively 0.005-0.1%, alternatively 0.05-0.1%, alternatively 0.01-0.1% of BHT, and water.
[0038] A nanoformulation as described above as an oral dosage form of cholecalciferol.
[0039] An oral dosage form of lipophilic actives comprising: nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants; an external phase comprising at least one nonionic surfactant; optionally pharmaceutically acceptable excipients in the nanoparticles and/or in the external phase; and water.
[0040] An oral dosage form of cholecalciferol comprising: nanoparticles comprising cholecalciferol, cremophor RH40, polysorbate80, and BHT; an external phase comprising polysorbate 80; and water, wherein the concentration of ingredients in the oral dosage form is 0.002-0.2% of cholecalciferol; 0.04-0.6% of cremophor RH40; 0.04-0.8% of polysorbate 80; and 0.0002-0.1% of BHT, optionally further comprising other excipients in the external phase as described herein. An oral dosage form of a lipophilic active/drug comprising: nanoparticles comprising cholecalciferol, cremophor RH40, polysorbate80, and BHT; an external phase comprising polysorbate 80; and water, wherein the concentration of ingredients in the oral dosage form is 0.002-0.2%, alternatively 0.001-0.2%, alternatively 0.05-0.2%, alternatively 0.001% of a lipophilic active/drug (e.g. cholecalciferol, clobazam, and/or ramipril); 0.04-0.6%, alternatively 0.05-0.6%, alternatively 0.1-0.5%, alternatively 0.05-0.5% of Cremophor RH40; 0.04- 0.8%, alternatively 0.02%-0.8%, alternatively 0.01%-0.8%, alternatively 0.1-0.8& of polysorbate 80; and 0.0002-0.1%, alternatively 0.0005-0.1%, alternatively 0.001-0.1%, alternatively 0.005-0.1%, alternatively 0.05-0.1%, alternatively 0.01-0.1% of BHT, , optionally further comprising other excipients in the external phase as described herein.
[0041] A process for the preparation of a stable nanoformulation comprising the steps of: a) preparing a nano-preconcentrate by adding a lipophilic active into at least a first nonionic surfactant and a first quantity of a second nonionic surfactant, mixing and solubilizing the active and optionally adding an excipient into the above mixture under stirring; b) preparing an external phase solution with at least a second quantity of said second nonionic surfactant, optionally further adding a third surfactant and/or an aqueous solution with other ingredients/excipients and homogenizing; c) adding said preconcentrate into said external phase solution under stirring and optionally adding aqueous solution with other ingredients/excipients and homogenizing, then allowing primary stabilization of this mixture under stirring; and d) adding water to make up the volume and secondary stabilization of final formulation under stirring. [0042] In some embodiments, the nonionic surfactants are selected from the group comprising PEG-40 Hydrogenated Castor Oil (Cremophor® RH40), Polysorbate 80, Polyoxyl castor oil, Ethoxylated sorbitan esters (Polysorbate 80, Polysorbate 20 and Polysorbate 60), polyethylene Glycol derivatives, Span series, Brij series of surfactants. Preferably, the nonionic surfactants are selected from the group comprising PEG-40 Hydrogenated Castor Oil, Polysorbate 20, Span 20, Polysorbate 80, Polyoxyl castor oil, Polysorbate 60, and combinations thereof. The surfactant may be present in the composition in an amount in the range from about 0.01% w/v to about 1.5% w/v.
[0043] In one embodiment, the nonionic surfactants are cremophor and polysorbate. The ratio of Cremophor to Polysorbate can range from about 20:80 to about 80:20.
[0044] In some embodiments, the pharmaceutically acceptable excipients are selected from the group comprising: sweeteners, flavoring agents, preservatives, antioxidants, pH modifiers, coloring agents, and combinations thereof.
[0045] Examples of suitable sweeteners which can be used in the present invention are selected from, but are not limited to, the group comprising: sucralose, maltitol, lactose anhydrous and sucrose. In one embodiment, the sweetener is present in the nanoemulsion in an amount in the range from about 0.050 to 67% w/v, preferably 0.066 to 0.6%, more preferably less than 1% w/v.
[0046] Flavoring agents suitable to be used in the present invention can be selected from, but are not limited to, the group comprising: Pineapple flavor RSV, citrus flavor family, preferably, pineapple, pineapple mango, Ginger pineapple, Pineapple orange, Pineapple grapefruit, Fresh cut pineapple, and combinations thereof. In one embodiment, the flavoring agents are present in the nanoemulsion in an amount selected from the range of 0.0013 to 0.2% w/v.
[0047] Some preservatives suitable to be used in the present nanoformulation can be selected from, but are not limited to, the group comprising: Potassium Sorbate, class of sorbates, benzoates, parabens, benzyl alcohol, cresols, phenols, Quaternary ammoniums, and combinations thereof. In one embodiment, the preservatives are present in the nanoemulsion in an amount selected from the range of about 0.02 to 1.0% w/v.
[0048] Suitable antioxidants to be used in the present invention can be selected from, but are not limited to, the group comprising: Disodium EDTA, BHT, Disodium EDTA, BHT, Tocopherol Acetate, TPGS (with linker of 1000 and 2000), Ascorbic acid, Sodium Metabisulphite, BHA, and combinations thereof. In one embodiment, the antioxidants are present in the nanoemulsion in an amount in the range of about 0.00002 to 0.5% w/v.
[0049] Examples of suitable coloring agents can be select from, but are not limited to, the group comprising: tartrazine yellow, FD&C Yellow No. 5, FD&C Yellow No. 6, FD&C Yellow No. 10. In one embodiment, the coloring agents are present in the nanoemulsion in an amount in the range of about 0.0001 to 0. l%w/v.
[0050] In one embodiment, an anionic surfactant is optionally added to the nanoformulation. Suitable anionic surfactants to be added can be selected from the group comprising: SDS (sodium dodecyl sulfate), SLES (sodium laureth sulfate) and Docusate, wherein the anionic surfactants are present in the nanoemulsion in an amount in the range of about 0.003 to 0.8% w/v.% w/v, alternatively about 0.005 to 0.8% w/v.% w/v, alternatively about 0.01 to 0.8% w/v.% w/v, alternatively 0.005 to 0.7% w/v.% w/v.
[0051] In one embodiment, the nanoformulation is an oral dosage form.
[0052] In one embodiment, the invention provides an oral dosage form of lipophilic actives comprising:
- nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants;
- an external phase comprising at least one nonionic surfactant;
- optionally pharmaceutically acceptable excipients in the nanoparticles and/or in the external phase; and
- water.
[0053] In one embodiment the process for the preparation of a stable nanoformulation comprises the steps of: a) addition of a lipophilic active into at least a first nonionic surfactant and a second nonionic surfactant; b) mixture and solubilizing the active; c) addition of an antioxidant into the above mixture under stirring, thus forming a nano- preconcentrate; d) addition of said preconcentrate into a second quantity of said second nonionic surfactant under stirring (external phase solution); e) primary stabilization of external phase mixture under stirring; f) sequential addition of aqueous solution of other ingredients/excipients to said final external phase; and g) final addition of water to make up the volume and secondary stabilization of final formulation under stirring.
[0054] In one embodiment, the process comprises the steps of: a) addition of a lipophilic active into a first nonionic surfactant and a second nonionic surfactant, this second surfactant being present at 70-80% of its total concentration in the final formulation; b) mixture and solubilizing the active/drug at 30-45°C; c) addition of an antioxidant into the above mixture under stirring, thus forming a nano-preconcentrate; d) addition of the preconcentrate to an external phase comprising a second quantity of said second nonionic surfactant (remaining 20-30%), under continuous stirring and maintaining the temperature at 30-50°C during addition of the preconcentrate; e) primary stabilization of external phase mixture under stirring for time period up to 8 hours; f) sequential addition of aqueous solution of all other ingredients/excipients to final external phase; and g) final addition of water to make up the volume (q.s.) and secondary stabilization of final formulation under stirring for time period up to 8 hours.
[0055] The second non-ionic surfactant is added in external phase based on HLB value (hydrophilic lipophilic balance, or the size and strength of the hydrophilic and lipophilic moi eties of a surfactant molecule). The higher the HLB, the higher the chances that an oil-in-water emulsion is formed. Accordingly, the second non-ionic surfactant is added for higher HLB in the external phase. Also, the remaining 20-30% of non-ionic surfactant is added in external phase to improve dispersibility of the core by lowering surface tension of external medium, which would not be true in case of plain aqueous system as it depicts high surface tension and thus would hinder the dispersibility process. [0056] In one embodiment, the duration of said stirring ranges for primary stabilization up to 8 hours and secondary stabilization from up to 8 hours. The stirring is a center vortex stirring. The speed of stirring can range from about 200 RPM to about 1000 RPM.
[0057] The examples shown herein below are intended to exemplify some of the ways of carrying out the invention, however without limiting its scope.
Examples
[0058] The following examples are included to demonstrate embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.
[0059] The experiments described in the following examples were designed to prove the physical stability of the nanosystem without NVVEP, according to the present invention.
[0060] The experiments herein described involved the following steps/objectives: i. To establish the impact of addition of NVVEP on the particle size of nanosystem; ii. To establish the surface charge stability-based stabilization; iii. To establish the storage stability of the formulations with and without NVVEP and impact of surface charge stabilization on storage stability (Physical stability).
Example 1 - Nanoformulation with NVVEP
[0061] The formula and procedure of comparative example A is depicted below:
Formula A: Nanosystem with NVVEP component (Strength 60000IU/5ml & 7000 IU/5ml)
Figure imgf000012_0001
Figure imgf000013_0001
Strength 400 IU/0.5 ml
Figure imgf000013_0002
Description of the process of preparation: Addition of cholecalciferol into Cremophor RH 40, polysorbate (80% of its quantity) and BHT; mixture to dissolve the active under stirring (Preconcentrate); 2. Addition of preconcentrate into external phase solution (remaining 20% of polysorbate) under continuous stirring (Final external phase);
3. Sequential addition of aqueous solution of all other ingredients to final external phase;
4. Final addition of water to make up the volume (q.s.).
Example 2 - Nanoformulation without NVVEP
[0063] The formula of a nanoformulation according to this embodiment of the invention is shown below:
Formula 1: Non-Surface Charge Stabilized (Non-SCS) Nanosystem without
NWEP component (Strength 60000IU/5ml & 7000 IU/5ml)
Figure imgf000014_0001
Strength 400 IU/0.5 ml
Figure imgf000014_0002
Figure imgf000015_0001
[0064] Description of the process of preparation:
1. Addition of cholecalciferol into Cremophor RH 40, polysorbate (80% of its quantity) and BHT mixture to dissolve the active under stirring (Preconcentrate);
2. Addition of preconcentrate into external phase solution (remaining 20% of polysorbate) under continuous stirring (Final external phase);
3. Sequential addition of aqueous solution of all other ingredients to final external phase;
4. Final addition of water to make up the volume (q.s.).
Example 3 - Nanoformulation surface charge stabilized without NVVEP
[0065] The formula and the process for preparing a nanoformulation with improved physical stability by means of surface charge stability according to this embodiment of the invention are shown below:
Formula 2: Surface Charge Stabilized (SCS) Nanosystem without NVVEP component (Strength 60000IU/5ml & 7000 IU/5ml)
Figure imgf000015_0002
Figure imgf000016_0001
Strength 400 IU/0.5 ml
Figure imgf000016_0002
[0066] Description of the process of preparation:
1. Addition of cholecalciferol into Cremophor RH 40, polysorbate (80% of its quantity) and BHT; mixture to dissolve the active under stirring (Preconcentrate);
2. Preparation of external phase solution (Sodium Dodecyl Sulphate and remaining 20% of polysorbate) in water;
3. Addition of preconcentrate into external phase solution under continuous stirring (Final external phase); 4. Sequential addition of aqueous solution of all other ingredients to final external phase;
5. Final addition of water to make up the volume (q.s).
Example 4 - Physical stability and particle size
[0067] The physical stability in terms of particle size was observed for 1 month at room temperature and accelerated condition (40°C/75%RH), the obtained results being shown below.
Formula A: Nanosystem with NVVEP component
Figure imgf000017_0001
Formula 1: Non-Surface Charge Stabilized (Non-SCS) Nanosystem without NVVEP component
Figure imgf000017_0002
Formula 2: SCS Nanosystem without NVVEP component
Figure imgf000017_0003
Observations and Remarks:
[0068] In case of the Nanosystem with NVVEP (Formula A), the particle size reduction was observed with respect to Non-SCS (Formula 1), and it was maintained for storage stability. In the alternate nanosystem strategy, we surprisingly found that NVVEP does not influence particle size in SCS Nanosystem (Formula 2), wherein we observed that with and without NVVEP, the particle size remains unaltered. For Non- SCS, observed particle size is larger than that of the formulation with NVVEP, but the effect on storage stability is negligible as the particle size does not significantly increase with time. [0069] Also, in case of SCS, the particle size (indicative of physical stability) is not impacted with storage time as measured for one month at room temperature and accelerated condition.
Example 5 - Oral dosage form of cholecalciferol
[0070] This embodiment provides an oral dosage form of cholecalciferol as described in example 4, comprising: nanoparticles comprising cholecalciferol, cremophor RH 40, polysorbate 80 and BHT; an external phase comprising polysorbate 80 and other excipients; and water.
[0071] The table below shows the data pertaining to physical stability of this embodiment of the invention in the absence or presence of NVVEP at different conditions.
[0072] Particle size (in nm) of the formulation of this embodiment with both strategy 1 (without NVVEP) and Strategy 2 (with NVVEP):
Figure imgf000018_0001
[0073] As shown in the results above, the physical stability of the formulation is neither dependent on the viscosity of external phase nor on the presence of NVVEP ingredients.
Example 6 - Nanoformulation with other lipophilic active ingredients
[0074] The effectiveness of the present invention was also shown with other lipophilic actives besides cholecalciferol. The present example uses clobazam and ramipril (two different categories of drugs) to evaluate their potential and applicability in the nanoformulation of the present invention. The results show that the nanoformulation of the invention is also functional and useful for other lipophilic actives/molecules. In one embodiment, this is feasible with the same concentrations and excipients that were also tested for cholecalciferol. The following are examples of the obtained results:
Figure imgf000019_0001
[0075] Formula of this embodiment of the Invention:
[0076] The formula 3 below discloses qualitative and quantitative composition (%w/v) and can be used different lipophilic actives/drugs:
Formula 3: Nanosystem without NVVEP component
Figure imgf000019_0002
Formula B: Nanosystem with NVVEP component
Figure imgf000019_0003
Figure imgf000020_0001
[0077] Manufacturing Procedure:
[0078] The manufacturing procedure for the formulation, inclusive of all actives/drugs/molecules explored, is as follows:
1. Addition of drug into Cremophor RH 40 and polysorbate (70-80% of its total quantity) mixture and solubilizing the drug at 30-45°C temperature (this temperature is critical for physical stability);
2 BHT is dissolved in above mixture under stirring and Nano-Preconcentrate is formed;
3. Addition of preconcentrate into external phase solution of polysorbate (remaining 20-30% of its total quantity) under continuous stirring (Centre vortex stirring) which is maintained at temperature of 30-50°C during addition of preconcentrate. Note that the addition of preconcentrate is also a critical process, where physical stability of the formulation is dependent on the rate of addition of preconcentrate;
4. Primary stabilization of external phase mixture under stirring for time period up to 8 hours;
5. Sequential addition of aqueous solution of all other ingredients/Excipients to final external phase;
6. Final addition of water to make up the volume (q.s.) and secondary stabilization of final formulation under stirring for time period up to 8 hours. ILLUSTRATIVE EMBODIMENTS
[0079] Provided here are illustrative embodiments of the disclosed technology. These embodiments are illustrative only and do not limit the scope of the present disclosure or of the claims attached.
[0080] Embodiment 1. A stable nanoformulation comprising: nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants; an external phase comprising at least one nonionic surfactant; optionally pharmaceutically acceptable excipients in the nanoparticles and/or in the external phase; and water. In certain embodiments, the lipophilic active ingredient may be cholecaliferol, clobazam, or ramipril.
[0081] Embodiment 2. The stable nanoformulation according to embodiment 1, wherein no phase viscosity stabilizer is used in the external phase.
[0082] Embodiments. The stable nanoformulation according to embodiment 1 or 2, wherein the nanoparticle range in size less than 500 nm.
[0083] Embodiment 4. The stable nanoformulation according to embodiment 1, 2 or 3, wherein the zeta potential is between lOmV and -lOmV.
[0084] Embodiment 5. The stable nanoformulation according to any one of embodiments 1-4, wherein the lipophilic active is selected from the group comprising: D vitamins, benzodiazepines and angiotensin converting enzyme inhibitor, cholecalciferol, clobazam, Ramipril, or combinations thereof.
[0085] Embodiment 6. The stable nanoformulation according any one of embodiments 1-5, wherein the nonionic surfactants are selected from PEG-40 Hydrogenated Castor Oil, Polysorbate 80, Polyoxyl castor oil, Ethoxylated sorbitan esters, polyethylene Glycol derivatives, Span series, Brij series of surfactants or combinations thereof.
[0086] Embodiment 7. The stable nanoformulation according to any one of embodiments 1-6, wherein the nonionic surfactants are in the range of from 0.01% w/v to 1.5% w/v.
[0087] Embodiment 8. The stable nanoformulation according to any one of embodiments 1-7, wherein the pharmaceutically acceptable excipients are selected from the group comprising: sweetener, flavoring agent, preservative, antioxidant, pH modifiers, coloring agents, or combinations thereof.
[0088] Embodiment 9. The stable nanoformulation according to any one of embodiments 1-8 further comprising an anionic surfactant.
[0089] Embodiment 10. The stable nanoformulation according to embodiment 9, wherein the anionic surfactant is selected from the group comprising: sodium dodecyl sulfate, sodium laureth sulfate and docusate, and combinations thereof.
[0090] Embodiment 11. The stable nanoformulation according to any one of embodiments 1-10, comprising: 0.002-0.2% of a lipophilic active/drug; 0.04-0.6% of cremophor RH40; 0.04-0.8% of polysorbate 80; and 0.0002-0.1% ofBHT, and water.
[0091] Embodiment 12. The stable nanoformulation according to embodiment 11, further comprising: 0.2-0.6% sucralose; 20-40% of maltitol; 1-4% of anhydrous lactose; 0.1-0.3% of potassium sorbate; 0.04-0.2% of disodium EDTA; 0.01-0.04% of citric acid monohydrate; 0.002-0.001% of tartrazine yellow; and 0.04-0.2% of pineapple flavor RSV
[0092] Embodiment 13. The stable nanoformulation according to embodiment 11, further comprising: 33.33-66.55% of sucrose; 0.066-0.266% of potassium sorbate; 0.013-0.066% of disodium EDTA; 0.003-0.013% of citric acid monohydrate; 0.013- 0.1% of pineapple flavor RSV.
[0093] Embodiment 14. The stable nanoformulation according to any one of embodiments 1-13 as an oral dosage form of cholecalciferol.
[0094] Embodiment 15. The stable nanoformulation according to any one of embodiments 1-13 as an oral dosage form of clobazam or ramipril.
[0095] Embodiment 16. The stable nanoformulation according to any one of embodiments 1-15, wherein the nanoformulation does not comprise a nondispersion vehicle imparting viscosity to an external phase.
[0096] Embodiment 17. An oral dosage form of lipophilic actives comprising: nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants; an external phase comprising at least one nonionic surfactant; optionally pharmaceutically acceptable excipients in the nanoparticles and/or in the external phase; and water.
[0097] Embodiment 18. The oral dosage form according to embodiment 17 wherein the lipophilic active is cholecalciferol.
[0098] Embodiment 19. The oral dosage form according to embodiment 17 wherein the lipophilic active is clobazam and/or ramipril. [0099] Embodiment 20. Oral dosage form of cholecalciferol comprising: nanoparticles comprising cholecalciferol, cremophor RH40, polysorbate80, and BHT; an external phase comprising polysorbate 80; and water, wherein the concentration of ingredients in the oral dosage form is 0.002-0.2% of cholecalciferol; 0.04-0.6% of cremophor RH40; 0.04-0.8% of polysorbate 80; and0.0002-0.1% of BHT.
[0100] Embodiment 21. The oral dosage form of any one of embodiments 17-20, wherein the dosage form does not comprise a nondispersion vehicle imparting viscosity to an external phase.
[0101] Embodiment 22. A process for the preparation of a stable nanoformulation comprising the steps of: a) preparing a nano-preconcentrate by adding a lipophilic active into at least a first nonionic surfactant and a first quantity of a second nonionic surfactant, mixing and solubilizing the active and optionally adding an excipient into the above mixture under stirring; b) preparing an external phase solution with at least a second quantity of said second nonionic surfactant, optionally further adding a third surfactant and/or an aqueous solution with other ingredients/excipients and homogenizing; c) adding said preconcentrate into said external phase solution under stirring and optionally adding aqueous solution with other ingredients/excipients and homogenizing, then allowing primary stabilization of this mixture under stirring; and d) adding water to make up the volume and secondary stabilization of final formulation under stirring.
[0102] Embodiment 23. A process according embodiment 22 wherein:
- said second nonionic surfactant is added in the preconcentrate at 70-80% of its total quantity in the final formulation;
- the step of mixture and solubilizing the active is performed at 30-45°C;
- addition of the preconcentrate into external phase solution comprising said second quantity of the second nonionic surfactant is performed at a temperature of 30-50°C;
- said primary stabilization of external phase mixture under stirring is performed for up to 8 hours; and/or
- the secondary stabilization of final formulation under stirring is made for up to 8 hours. In variations of embodiment 20, the process includes each of these steps. Alternatively, the process includes one, two, three, or four of these steps.
[0103] Embodiment 24. A process according embodiment 22 comprising the steps of:
- addition of the lipophilic active/drug into Cremophor RH 40 and polysorbate (70-80% of its total quantity) mixture and solubilizing the drug at 30-45°C temperature;
- dissolution of BHT in above mixture under stirring, and formation of a nano- preconcentrate;
- addition of a nano-preconcentrate into external phase solution of polysorbate (remaining 20-30% of its total quantity) under continuous stirring and temperature maintained at 30-50°C during addition of the nano-preconcentrate;
- primary stabilization of external phase mixture under stirring for time period up to 8 hours;
- sequential addition of aqueous solution of all other ingredients/excipients to a final external phase; and
- final addition of water to make up the volume (q.s.) and secondary stabilization of final formulation under stirring for time period up to 8 hours.
[0104] While the illustrative embodiments of the invention have been described with detail, those skilled in the art will appreciate the teachings presented herein and will be able to reproduce the invention in the modalities presented and in other variants and alternatives, covered by the scope of the following claims.

Claims

Claims What is claimed is:
1. A stable nanoformulation comprising:
- nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants;
- an external phase comprising at least one nonionic surfactant;
- optionally pharmaceutically acceptable excipients in the nanoparticles and/or in the external phase; and
- water.
2. The stable nanoformulation according to claim 1, wherein no phase viscosity stabilizer is used in the external phase.
3. The stable nanoformulation according to claim 1 or 2, wherein the nanoparticles range in size less than 500 nm.
4. The stable nanoformulation according to claim 1, 2 or 3, wherein the zeta potential is between lOmV and -lOmV.
5. The stable nanoformulation according to any one of claims 1-4, wherein the lipophilic active is selected from the group comprising: D vitamins, benzodiazepines and angiotensin converting enzyme inhibitor, chol ecalciferol, clobazam, Ramipril, or combinations thereof.
6. The stable nanoformulation according any one of claims 1-5, wherein the nonionic surfactants are selected from PEG-40 Hydrogenated Castor Oil, Polysorbate 80, Polyoxyl castor oil, Ethoxylated sorbitan esters, polyethylene Glycol derivatives, Span series, Brij series of surfactants or combinations thereof.
7. The stable nanoformulation according to any one of claims 1-6, wherein the nonionic surfactants are in the range of from 0.01% w/v to 1.5% w/v.
24
8. The stable nanoformulation according to any one of claims 1-7, wherein the pharmaceutically acceptable excipients are selected from the group comprising: sweetener, flavoring agent, preservative, antioxidant, pH modifiers, coloring agents, or combinations thereof.
9. The stable nanoformulation according to any one of claims 1-8 further comprising an anionic surfactant.
10. The stable nanoformulation according to claim 9, wherein the anionic surfactant is selected from the group comprising: sodium dodecyl sulfate, sodium laureth sulfate and docusate, and combinations thereof.
11. The stable nanoformulation according to any one of claims 1-10, comprising: 0.002-0.2% of a lipophilic active/drug; 0.04-0.6% of cremophor RH40; 0.04-0.8% of polysorbate 80; and 0.0002-0.1% of BHT, and water.
12. The stable nanoformulation according to claim 11, further comprising: 0.2- 0.6% sucralose; 20-40% of maltitol; 1-4% of anhydrous lactose; 0.1-0.3% of potassium sorbate; 0.04-0.2% of disodium EDTA; 0.01-0.04% of citric acid monohydrate; 0.002- 0.001% of tartrazine yellow; and 0.04-0.2% of pineapple flavor RSV.
13. The stable nanoformulation according to claim 11, further comprising: 33.33- 66.55% of sucrose; 0.066-0.266% of potassium sorbate; 0.013-0.066% of disodium EDTA; 0.003-0.013% of citric acid monohydrate; and 0.013-0.1% of pineapple flavor RSV
14. The stable nanoformulation according to any one of claims 1-13 as an oral dosage form of chol ecalciferol.
15. The stable nanoformulation according to any one of claims 1-13 as an oral dosage form of clobazam or ramipril.
16. The stable nanoformulation according to any one of claims 1-15, wherein the nanoformulation does not comprise a nondispersion vehicle imparting viscosity to an external phase.
17. An oral dosage form of lipophilic actives comprising:
- nanoparticles comprising at least one lipophilic active ingredient and at least two nonionic surfactants;
- an external phase comprising at least one nonionic surfactant;
- optionally pharmaceutically acceptable excipients in the nanoparticles and/or in the external phase; and
- water.
18. The oral dosage form according to claim 17 wherein the lipophilic active is cholecalciferol.
19. The oral dosage form according to claim 17 wherein the lipophilic active is clobazam and/or ramipril.
20. Oral dosage form of cholecalciferol comprising:
- nanoparticles comprising cholecalciferol, cremophor RH40, polysorbate80, and BHT;
- an external phase comprising polysorbate 80; and
- water, wherein the concentration of ingredients in the oral dosage form is
- 0.002-0.2% of cholecalciferol;
- 0.04-0.6% of cremophor RH40;
- 0.04-0.8% of polysorbate 80; and
- 0.0002-0.1% of BHT.
21. The oral dosage form of any one of claims 17-20, wherein the dosage form does not comprise a nondispersion vehicle imparting viscosity to an external phase.
22. A process for the preparation of a stable nanoformulation comprising the steps of: a) preparing a nano-preconcentrate by adding a lipophilic active into at least a first nonionic surfactant and a first quantity of a second nonionic surfactant, mixing and solubilizing the active and optionally adding an excipient into the above mixture under stirring; b) preparing an external phase solution with at least a second quantity of said second nonionic surfactant, optionally further adding a third surfactant and/or an aqueous solution with other ingredients/excipients and homogenizing; c) adding said preconcentrate into said external phase solution under stirring and optionally adding aqueous solution with other ingredients/excipients and homogenizing, then allowing primary stabilization of this mixture under stirring; and d) adding water to make up the volume and secondary stabilization of final formulation under stirring.
23. A process according claim 22 wherein:
- said second nonionic surfactant is added in the preconcentrate at 70-80% of its total quantity in the final formulation;
- the step of mixture and solubilizing the active is performed at 30-45°C;
- addition of the preconcentrate into external phase solution comprising said second quantity of the second nonionic surfactant is performed at a temperature of 30- 50°C;
- said primary stabilization of external phase mixture under stirring is performed for up to 8 hours; and/or
- the secondary stabilization of final formulation under stirring is made for up to 8 hours.
27
24. A process according claim 22 comprising the steps of:
- addition of the lipophilic active/drug into Cremophor RH 40 and polysorbate (70-80% of its total quantity) mixture and solubilizing the drug at 30-45°C temperature;
- dissolution of BHT in above mixture under stirring, and formation of a nano- preconcentrate;
- addition of the nano-preconcentrate into external phase solution of polysorbate (remaining 20-30% of its total quantity) under continuous stirring and temperature maintained at 30-50°C during addition of the nano-preconcentrate;
- primary stabilization of external phase mixture under stirring for time period up to 8 hours;
- sequential addition of aqueous solution of all other ingredients/excipients to a final external phase; and
- final addition of water to make up the volume (q.s.) and secondary stabilization of final formulation under stirring for time period up to 8 hours.
28
PCT/IB2021/062069 2021-12-21 2021-12-21 Stable nanoformulation for lipophilic actives, oral dosage form and process for its preparation WO2023118928A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2021/062069 WO2023118928A1 (en) 2021-12-21 2021-12-21 Stable nanoformulation for lipophilic actives, oral dosage form and process for its preparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2021/062069 WO2023118928A1 (en) 2021-12-21 2021-12-21 Stable nanoformulation for lipophilic actives, oral dosage form and process for its preparation

Publications (1)

Publication Number Publication Date
WO2023118928A1 true WO2023118928A1 (en) 2023-06-29

Family

ID=80222413

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2021/062069 WO2023118928A1 (en) 2021-12-21 2021-12-21 Stable nanoformulation for lipophilic actives, oral dosage form and process for its preparation

Country Status (1)

Country Link
WO (1) WO2023118928A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1249231A1 (en) * 2001-04-12 2002-10-16 Vesifact Ag Pharmaceutical formulations comprising anti-inflammatory compounds and use thereof
WO2010111397A1 (en) * 2009-03-24 2010-09-30 Adds Pharmaceuticals Llc Stabilized solubility-enhanced formulations for oral delivery
WO2015155703A2 (en) 2014-04-09 2015-10-15 Nanoceutica Laboratories Pvt. Ltd Composition and method of producing nanoformulation of water insoluble bioactives in aqueous base
KR20200046676A (en) * 2018-10-25 2020-05-07 단국대학교 천안캠퍼스 산학협력단 Complex liquid fomulation comprising vitamin D emulsion and bisphosphonate and use for preventing or treating osteoporosis

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1249231A1 (en) * 2001-04-12 2002-10-16 Vesifact Ag Pharmaceutical formulations comprising anti-inflammatory compounds and use thereof
WO2010111397A1 (en) * 2009-03-24 2010-09-30 Adds Pharmaceuticals Llc Stabilized solubility-enhanced formulations for oral delivery
WO2015155703A2 (en) 2014-04-09 2015-10-15 Nanoceutica Laboratories Pvt. Ltd Composition and method of producing nanoformulation of water insoluble bioactives in aqueous base
KR20200046676A (en) * 2018-10-25 2020-05-07 단국대학교 천안캠퍼스 산학협력단 Complex liquid fomulation comprising vitamin D emulsion and bisphosphonate and use for preventing or treating osteoporosis

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CARPENTER ET AL.: "Formation and surface-stabilizing contributions to bare nanoemulsions created with negligible surface charge", PNAS, vol. 116, no. 19, 7 May 2019 (2019-05-07), pages 9214 - 9219
ZENG L.: "Development and characterization of promising Cremophor EL-stabilized o/w nanoemulsions containing short-chain alcohols as a cosurfactant", RSC ADV., vol. 7, 2017, pages 19815 - 19827, XP055765916, DOI: 10.1039/C6RA27096D

Similar Documents

Publication Publication Date Title
Fatouh et al. Intranasal agomelatine solid lipid nanoparticles to enhance brain delivery: formulation, optimization and in vivo pharmacokinetics
US6960563B2 (en) Spontaneous emulsions containing cyclosporine
Trotta et al. Preparation of griseofulvin nanoparticles from water-dilutable microemulsions
EP2358355B1 (en) Pharmaceutical composition of a potent hcv inhibitor for oral administration
EP3582750A1 (en) Oral cannabinoid formulations
US8252326B2 (en) Self-microemulsifying dosage forms of low solubility active ingredients such as co-enzyme Q10
Sriamornsak et al. A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution
EP1242047B1 (en) Fenofibrate galenic formulations and method for obtaining same
EP2600838B1 (en) Pharmaceutical dosage form comprising 6'-fluoro-(n-methyl- or n,n-dimethyl-)-4-phenyl-4',9'-dihydro-3'h-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine
CN117695226A (en) Compositions for delivering therapeutic agents, methods of use and methods of preparation thereof
CA3050013A1 (en) Method of preparation of cannabinoids containing beverages
AU2002356137A1 (en) Spontaneous emulsions containing cyclosporine
ES2321912T3 (en) FORMULATIONS IN PHENOFIBRATE NANOPARTICLES.
KR20160101167A (en) Racecadotril compositions
JPH04226911A (en) Stable emulsion suitable for pharmaceutical administration, method of its preparation and emulsion to be used as drug
Cavanak et al. Formulation of dosage forms
JP2003525893A (en) Novel self-emulsifying drug delivery system
Abdelhakeem et al. Lipid-based nano-formulation platform for eplerenone oral delivery as a potential treatment of chronic central serous chorioretinopathy: in-vitro optimization and ex-vivo assessment
Hyma et al. Formulation and characterisation of self-microemulsifying drug delivery system of pioglitazone
WO2023118928A1 (en) Stable nanoformulation for lipophilic actives, oral dosage form and process for its preparation
CN109640948B (en) Chemical composition
US20230310465A1 (en) Nano lipid carrier system for improving permeation of active ingredients
Qader et al. Novel oral solid self-nanoemulsifying drug delivery system (S-SNEDDS) of rosuvastatin calcium: Formulation, characterization, bioavailability and pharmacokinetic study
Jena et al. A Review on Game-changing approach for the Oral Administration of Lipophilic Drug: SEDDS
Bhagwat et al. Development of solid self micro emulsifying formulation to improve oral bioavailability

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21854821

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE