Nilotinib Granule Composition With Extragranular Surfactant Stability
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Solution Overview
Problem
Existing pharmaceutical compositions and dosage forms of Nilotinib, particularly crystalline anhydrous Nilotinib hydrochloride or crystalline Nilotinib hydrochloride monohydrate, are not satisfactory in terms of compatibility with excipients and do not effectively enhance bioavailability and stability.
Innovation Solution
Formulating Nilotinib in an intragranular phase with an extragranular surfactant, such as poloxamer, in a separate phase, ensuring homogenous distribution through geometric dilution, which maintains the anhydrous nature of lactose and improves solubility and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If common excipients like lactose, microcrystalline cellulose, and mannitol are used in Nilotinib formulations, then the formulation can be manufactured, but high polymorphic conversion occurs and stability is compromised
Solution Approach 1:
The patent removes incompatible excipients (lactose, microcrystalline cellulose, mannitol) from the formulation and replaces them with compatible alternatives like anhydrous sucrose, creating a stable formulation that prevents polymorphic conversion while maintaining manufacturability
Solution Approach 2:
The patent creates a composite granule system combining Nilotinib with specifically selected compatible excipients (anhydrous sucrose, pregelatinized starch, crosslinked sodium carboxymethyl cellulose) that work together to maintain polymorphic stability and prevent conversion to unwanted crystal forms
2Productivity
If Nilotinib is formulated with traditional excipients, then the dosage form can be produced, but bioavailability is not effectively enhanced
Solution Approach 1:
The patent modifies the physical and chemical parameters of the formulation by using anhydrous conditions, specific granulation methods, and compatible excipients that enhance solubility and dissolution rate, thereby improving bioavailability without compromising manufacturing efficiency
Solution Approach 2:
The patent applies surfactants locally at the granule surface and within the granule matrix to create microenvironments that enhance drug dissolution and absorption, improving bioavailability while maintaining overall formulation manufacturability
3Reliability
If surfactant is incorporated into granules, then solubility is enhanced, but compatibility issues and polymorphic conversion increase
Solution Approach 1:
The patent uses compatible excipients like anhydrous sucrose and pregelatinized starch as intermediaries between Nilotinib and surfactants, allowing surfactant incorporation for solubility enhancement while preventing direct interactions that would cause polymorphic conversion
Solution Approach 2:
The patent controls the physical state and concentration of surfactants, using them in anhydrous granulation conditions with specific amounts that enhance solubility without triggering polymorphic conversion, thereby maintaining both solubility enhancement and polymorphic stability
4Ease of manufacture
If wet granulation process is used, then granules can be formed, but water introduces stability and compatibility issues
Solution Approach 1:
The patent removes water from the granulation process entirely, replacing wet granulation with dry granulation methods that use no liquid binders, thereby eliminating water-induced stability and compatibility issues while still achieving effective granule formation
Solution Approach 2:
The patent changes the granulation process parameters from wet to dry conditions, using mechanical energy and compatible dry binders to form granules without water, thereby maintaining ease of manufacture while dramatically improving overall formulation stability
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The formulation achieves bioequivalence to commercial Tasigna® while maintaining stability and enhancing in vivo performance, with improved solubility and bioavailability of Nilotinib.
Implementation Method 1
an extragranular phase comprising a surfactant, wherein the surfactant is a poloxamer
Data Source
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AI summary
The invention relates to a pharmaceutical composition comprising (i) granules comprising Nilotinib, preferably in crystalline form, or a physiologically acceptable salt and/or solvate thereof, preferably crystalline anhydrous Nilotinib hydrochloride or crystalline Nilotinib hydrochloride monohydrate; and (ii) an extragranular phase comprising a surfactant, preferably poloxamer. The granules are preferably dry granulated.