Preparation of an oil-in-water emulsion for polymer stabilized pharmaceutical formulations
Inventors
Foreman, James Michael • Ukeje, Anayo Michael • Swank, Ronald W. • Wong, Waiken
Assignees
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Publication Number
US-10413508-B2
Publication Date
2019-09-17
Expiration Date
Abstract
An improved process for producing an oil-in-water emulsion to deliver a substantially water insoluble active pharmaceutical ingredient includes creating a microemulsion containing such ingredient in the oil phase of the emulsion by mixing an aqueous phase including non-ionic surfactant, polyol, and water, wherein the weight ratio of the surfactant to polyol to water is between 10:20:70 and 1:1:1, to generate a mixture, with an oil phase comprising a substantially water insoluble active pharmaceutical ingredient and a long-chain triglyceride; circulating the said mixture through a homogenizer at a temperature from 20° C. to 60° C. to generate a coarse emulsion; passing the coarse emulsion through a microfluidizer at a pressure of from 70 MPa to 150 MPa at least once to produce an oil-in-water microemulsion; and, optionally, filtering the microemulsion through a 0.2 μm filter and/or mixing the microemulsion with a polymeric stabilizer.
Core Innovation
The invention relates to an improved method of preparing a stable oil-in-water microemulsion for delivering a substantially water insoluble active pharmaceutical ingredient. The method generates a mixture by combining an aqueous phase comprising a non-ionic surfactant, a polyol, and water with an oil phase comprising the substantially water insoluble active pharmaceutical ingredient and a long-chain triglyceride.
The aqueous phase and oil phase are combined using defined weight ratios, such that the weight ratio of the oil phase to the aqueous phase is between about 0.01:1 and 1:1, and the weight ratio of the surfactant to polyol to water is between 10:20:70 and 1:1:1. The mixture is passed at least once through a homogenizer at a temperature of from about 20° C. to about 50° C. to generate a coarse emulsion.
The coarse emulsion is then passed at least once through a microfluidizer at a pressure of from about 70 MPa to about 150 MPa to produce an oil-in-water microemulsion having a mean oil particle droplet size of between about 50 nm and 300 nm. Additional refinements described include optional filtering and optional mixing with polymeric stabilizers to support stability of the resulting microemulsion.
Claims Coverage
The document includes one independent claim describing the overall method of preparing a stable oil-in-water microemulsion, with multiple dependent claims refining specific materials and process constraints. The independent claim contains inventive features centered on defined phase compositions/weight ratios, a two-stage size-reduction sequence (homogenizer followed by microfluidizer), and a droplet-size target for the microemulsion.
Defined aqueous and oil phase composition and weight ratios
Mixing an aqueous phase comprising a non-ionic surfactant, a polyol, and water to solubilize the surfactant and polyol in the aqueous phase, wherein the weight ratio of the surfactant to polyol to water is between 10:20:70 and 1:1:1, with an oil phase comprising a substantially water insoluble active pharmaceutical ingredient and a long-chain triglyceride to generate a mixture, wherein the weight ratio of the oil phase to the aqueous phase is between about 0.01:1 and 1:1.
Homogenization at a controlled temperature to generate a coarse emulsion
Passing the mixture produced in step (a) at least once through a homogenizer at a temperature of from about 20° C. to about 50° C. to generate a coarse emulsion.
Microfluidization at 70–150 MPa to obtain 50–300 nm droplet size
Passing the coarse emulsion at least once through a microfluidizer at a pressure of from about 70 MPa to about 150 MPa to produce an oil-in-water microemulsion having a mean oil particle droplet size of between about 50 nm and 300 nm.
Overall claim coverage is focused on producing a stable oil-in-water microemulsion by combining defined aqueous and oil phase components using specified weight ratios, generating a coarse emulsion by homogenization at 20–50° C., and producing a microemulsion with a mean oil droplet size of 50–300 nm via microfluidization at 70–150 MPa. Dependent claims further constrain or specify ingredients and add optional post-processing such as filtering.
Stated Advantages
Produces a stable oil-in-water microemulsion having a mean oil particle droplet size between about 50 nm and 300 nm.
Improves bioavailability of substantially water insoluble active pharmaceutical ingredients, as stated in the provided content.
Provides extended stability of the microemulsion, as stated in the provided content.
Documented Applications
Delivery/formulation context for substantially water insoluble active pharmaceutical ingredients using stable oil-in-water microemulsions, including cyclosporine as referenced in the provided content.
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