Bendamustine Oral Solid Dosage Forms with Saccharide Excipients
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Solution Overview
Problem
Bendamustine's existing intravenous formulation is unstable after reconstitution, leading to potency reduction and impurity formation, and its oral administration has low bioavailability and high variability due to incomplete absorption and difficult reconstitution process.
Innovation Solution
Development of stable oral solid dosage forms comprising bendamustine with pharmaceutically acceptable saccharides like mannitol, maltitol, erythritol, and lactose, which improve dissolution profile and bioavailability by forming tablets or granules with specific excipient ratios, ensuring rapid dissolution in the stomach to minimize degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If bendamustine is formulated as intravenous lyophilized powder requiring reconstitution, then it can be administered to patients, but the reconstitution process is difficult and time-consuming (more than 30 minutes) and the formulation becomes unstable after reconstitution leading to potency reduction and impurity formation
Solution Approach 1:
The patent changes the physical and chemical parameters of bendamustine by converting it from intravenous lyophilized powder to oral solid dosage forms (tablets, capsules, granules). This parameter change eliminates the reconstitution step entirely, as the drug is administered directly in oral form. The stability issue is resolved by formulating the drug in a stable solid state with appropriate excipients, avoiding the unstable reconstituted aqueous solution.
Solution Approach 2:
The patent extracts the problematic reconstitution step from the administration process by developing oral solid dosage forms that can be administered directly without requiring dissolution or reconstitution. This removes the source of instability and operational difficulty associated with the intravenous formulation's reconstitution process.
2Ease of operation
If bendamustine is administered orally in capsule form, then patient compliance improves, but bioavailability is low (57% mean, ranging from 25% to 94%) and shows large inter-individual variability due to incomplete absorption
Solution Approach 1:
The patent changes the formulation parameters by developing oral solid dosage forms with optimized composition and dissolution characteristics. The new formulation uses specific excipients and manufacturing processes to control drug release and dissolution rate, thereby improving and stabilizing bioavailability while maintaining the convenience of oral administration.
Solution Approach 2:
The patent creates composite oral dosage forms by combining bendamustine with specific excipients and additives that enhance dissolution and absorption. These composite materials are designed to improve the drug's solubility and dissolution rate, leading to more consistent and complete absorption in the gastrointestinal tract, thereby reducing inter-individual variability in bioavailability.
3Reliability
If bendamustine is administered as intravenous infusion, then complete bioavailability is achieved, but the formulation requires difficult reconstitution and must be administered immediately after reconstitution due to stability problems
Solution Approach 1:
The patent extracts and eliminates the time-consuming reconstitution step by developing oral solid dosage forms that are ready for administration immediately. Patients simply take the tablets or capsules with water, eliminating the 30+ minute reconstitution process required for intravenous formulation while maintaining effective drug delivery.
Solution Approach 2:
Instead of starting with a stable solid formulation that requires reconstitution to become active (intravenous route), the patent inverts the approach by creating an oral solid formulation where the drug remains stable in solid form and is activated through dissolution in the gastrointestinal tract. This inversion eliminates the need for hospital-based reconstitution while maintaining drug 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 new oral dosage forms provide enhanced stability, increased bioavailability, and reduced variability in bendamustine absorption, ensuring effective and consistent drug delivery with improved patient compliance.
Implementation Method 1
compositions which have an improved dissolution profile
Data Source
Figure 1
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AI summary
In the present invention there is provided a pharmaceutical composition in a solid dosage form suitable for oral administration, the composition comprising bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, which is a pharmaceutically acceptable saccharide selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a saccharide alcohol, wherein the ratio by weight of the active ingredient to the saccharide excipient(s) is in the range of 1 :1-5.