Controlled release pharmaceutical formulations of nitozoxanide
Inventors
Rossignol, Jean-Francois • Ayers, Marc
Assignees
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Publication Number
US-10383855-B2
Publication Date
2019-08-20
Expiration Date
Abstract
Solid dosage formulations of nitazoxanide or a nitazoxanide analog are provided that comprise a controlled release portion and an immediate release portion. The pharmaceutical composition is typically in the form of a bilayer solid oral dosage form comprising (a) a first layer comprising a first quantity of nitazoxanide or analog thereof in a controlled release formulation; and (b) a second layer comprising a second quantity of nitazoxanide or analog thereof in an immediate release formulation. Method of using the formulations in the treatment of hepatitis C are also provided.
Core Innovation
The invention relates to solid controlled-release pharmaceutical formulations of nitazoxanide, tizoxanide, or a combination thereof that include a controlled release portion and an immediate release portion. The compositions are described as a solid dosage form administered to a patient, with the objective of extending absorption. In particular, a first portion is formulated in a controlled release formulation and a second portion is formulated in an immediate release formulation.
The disclosed solid dosage form is exemplified as a bilayer oral tablet, including a first controlled-release layer and a second immediate-release layer. The controlled-release first portion and immediate-release second portion contain respective quantities of nitazoxanide, tizoxanide, or a combination thereof. In examples, the formulation includes a low-viscosity polymer binder in the controlled-release layer, including low-viscosity hydroxypropyl methylcellulose (Methocel).
The disclosure is directed to using the combined controlled-release and immediate-release composition to treat chronic hepatitis C by extending absorption and bioavailability while reducing gastrointestinal side effects from higher dosing. The document further describes relative quantities of the controlled and immediate portions using a controlled:immediate ratio of about 2.5–4:1, and clinical/PK findings showing increased tizoxanide exposure and improved tolerability versus an immediate-release tablet, together with improved virologic response outcomes in HCV genotype 4 patients.
Claims Coverage
The independent claim is directed to extending absorption of nitazoxanide, tizoxanide, or a combination thereof by administering a solid oral pharmaceutical composition that combines controlled-release and immediate-release formulations. The claim set includes dependent claim refinements that add specific formulation components, quantitative ratio constraints, and solid dosage form structure features.
Extending absorption with controlled release and immediate release solid dosage form
administering to the patient a therapeutically effective amount of a pharmaceutical composition in the form of a solid dosage form, wherein the composition comprises (a) a first portion comprising a first quantity of nitazoxanide, tizoxanide or a combination thereof in a controlled release formulation, and (b) a second portion comprising a second quantity of nitazoxanide, tizoxanide or a combination thereof in an immediate release formulation.
Controlled-to-immediate quantity ratio
the ratio of a first quantity to a second quantity is approximately 2.5:1 to approximately 4:1.
Bilayer tablet with controlled-release first layer and immediate-release second layer
a bilayer tablet in which a controlled-release first layer contains about 500 mg nitazoxanide with low-viscosity hydroxypropylmethylcellulose, and an immediate-release second layer containing about 175 mg nitazoxanide is deposited on top of and compressed with the first layer to form a core tablet.
Low viscosity polymer in controlled-release portion
adding a low viscosity polymer to the first portion.
Controlled-release and immediate-release granules
a first portion formulated as controlled-release granules with a first quantity of nitazoxanide and a second portion formulated as immediate-release granules with a second quantity of nitazoxanide.
Optional outer coating on core tablet
applying an outer coating (c) to the core tablet.
Overall, the claim coverage centers on extending absorption of nitazoxanide and/or tizoxanide using a solid dosage form that combines a controlled release portion with an immediate release portion, optionally implemented as a bilayer tablet and further defined by a low-viscosity polymer in the controlled-release portion and a specified controlled-to-immediate quantity ratio.
Stated Advantages
Extends absorption of nitazoxanide and/or tizoxanide in a patient.
Increased tizoxanide exposure versus an immediate-release 500 mg tablet.
Improved tolerability versus an immediate-release 500 mg tablet.
Improved virologic responses in HCV genotype 4 patients.
Possibility of dose escalation with fewer adverse events.
Documented Applications
Treatment of chronic hepatitis C (HCV) by extending absorption/bioavailability while reducing gastrointestinal side effects from higher dosing, including improved outcomes in HCV genotype 4 patients.
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