Formulations
Inventors
Fanara, Domenico • Berwaer, Monique • Guichaux, Anthony • Deleers, Michel
Assignees
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Publication Number
US-8946229-B2
Publication Date
2015-02-03
Expiration Date
Abstract
The present invention relates to pharmaceutical compositions for oral administration of active compounds.
Core Innovation
The document describes oral formulations for histamine H1-receptor antagonists comprising active compounds of Formula I, including 2-[4-(diphenylmethyl)-1-piperazinyl]-acetic acids and their amides. The formulations focus on chewable, mouth-dispersible oral dosage forms and include taste masking approaches.
A specific problem is identified in that undesired reaction products are generated from an interaction between the Formula I active compounds and certain polyols, with an association to decreasing polyol molecular weight. The document correlates this behavior with reactive polyol molecular weight ranges and defines reactive and very reactive polyol MW ranges and critical molar-ratio limits for polyol relative to the active compound of Formula I.
To address both taste and stability, the document discloses a two formulation approach for a chewable dosage form, including a first formulation in a first layer and a second, drug-free formulation in a second layer. The first layer excludes polyols having molecular weight below 300 by applying specific polyol-to-active molar-ratio limits, while the second layer contains one or more solid polyol(s) with molecular weight of less than 3000.
The document further describes using excipients for taste masking and formulation support, including cyclodextrin for taste masking and an alkalinizing agent such as sodium citrate, and reports stability and undesired reaction product results showing maintained specifications under accelerated storage and low reaction product formation.
Claims Coverage
The independent claim set includes one independent claim covering a chewable, two-layer tablet, with 9 inventive features defined by the Formula I active compound family, a two-layer structure with a drug-free second layer, exclusion of certain low-molecular-weight polyols from the first layer via polyol-to-active molar-ratio limits, inclusion of an alkalinizing agent, specific active compound options, excipient selections, and example polyol and alkalinizing agent choices.
Two-layer chewable tablet with drug-free second polyol layer
A chewable tablet pharmaceutical composition consisting of two layers, with a first layer containing a first formulation and a second layer containing a second formulation that is free of any drug.
Formula I histamine H1-receptor antagonist in first layer
The first layer contains an active compound selected from 2-[4-(diphenylmethyl)-1-piperazinyl]-acetic acids and their amides having the general formula I, with defined substituent meanings for R1, and X1 and X2, and including pharmaceutically acceptable salts, geometrical isomers, enantiomers, diastereomers and mixtures thereof.
Exclusion of reactive low-MW polyols from first layer by polyol-to-active molar ratio
The first layer does not contain polyols having a molecular weight of less than 300 in a molar ratio between the polyol and active compound of formula I above 10.
Solid polyol(s) with MW < 3000 in drug-free second layer
The second layer contains one or more solid polyol(s) with a molecular weight of less than 3000.
Alkalinizing agent in at least one formulation
At least one of the formulations further contains an alkalinizing agent.
Specific active compound options within Formula I
The first formulation specifies an active compound selected from cetirizine dihydrochloride, levocetirizine dihydrochloride, or efletirizine dihydrochloride.
Excipients selected from taste masking and formulation support categories
One or more excipients are selected from cyclodextrins, colloidal anhydrous silica, microcrystalline cellulose, magnesium stearate, flavors, or colorants.
Alkalinizing agent is sodium citrate
The alkalinizing agent is sodium citrate.
Second-layer solid polyol is mannitol
The polyol in the second formulation is mannitol.
Overall claim coverage centers on a chewable, two-layer tablet where a Formula I histamine H1-receptor antagonist is placed in a first layer under constraints that exclude low-molecular-weight polyols by applying polyol-to-active molar-ratio limits. The second layer is drug-free and contains solid polyol(s) of molecular weight less than 3000, and the formulations include an alkalinizing agent; dependent claims further specify active compounds, taste-masking and formulation excipient categories, and example selections such as sodium citrate as the alkalinizing agent and mannitol as the second-layer polyol.
Stated Advantages
Low reaction product formation.
Maintained specifications under accelerated storage conditions.
Mouth-dispersible performance.
Bioequivalence.
Taste masking.
Documented Applications
Chewable tablet pharmaceutical compositions for oral, mouth-dispersible delivery of histamine H1-receptor antagonists of Formula I.
Bi-layer tablets and other oral dosage forms including dry syrups and chewing gum are described in the document for the same active compound family and formulation concepts.
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