Pimobendan Formulation Using Malic Acid Microspheres
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Solution Overview
Problem
Existing pimobendan formulations face challenges with low solubility and pH-dependent absorption, leading to fluctuating blood concentrations and difficulties in administration, especially for small animals due to high hardness and size of tablets.
Innovation Solution
A novel solid formulation dispersing pimobendan in malic acid with copovidone, microcrystalline cellulose, and stearic acid, prepared through wet granulation, resulting in tablets or granules that are palatable and easier to swallow, with a process that includes mixing, granulating, drying, and compressing to form tablets or granules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pimobendan is formulated with high quantities of citric acid to overcome low solubility and pH-dependent absorption, then dissolution and absorption of pimobendan is improved, but the acidic taste is not readily accepted by animals and the formulation must be force-fed or mixed with food
Solution Approach 1:
The patent introduces an enteric coating as an intermediary layer between the acidic citric acid core and the animal's taste receptors. This coating mediates the contradiction by allowing the acidic core to maintain its pH-lowering function while preventing direct contact with the animal's taste buds, thus eliminating the acidic taste issue while preserving dissolution effectiveness
Solution Approach 2:
The patent changes the physical-chemical parameters of the formulation by using enteric-coated citric acid particles instead of plain citric acid. This parameter change (adding an enteric coating layer) transforms the formulation from one that is tasteful but ineffective to one that is both effective and palatable, as the coating prevents acid release until it reaches the intestinal tract
2Reliability
If pimobendan tablets are formulated with sufficient excipients to ensure stability and dissolution, then pharmaceutical performance is improved, but the tablets present large size and high hardness so that small animals spit them out
Solution Approach 1:
The patent applies segmentation by dividing the tablet into multiple smaller granules, each containing enteric-coated citric acid particles and pimobendan. This segmentation reduces the overall size and hardness of the dosage form while maintaining the total pharmaceutical performance through the combined effect of multiple granules, making it acceptable for small animals to swallow
Solution Approach 2:
The patent uses composite materials by combining enteric-coated citric acid particles with pimobendan and other excipients in a granulated matrix. This composite structure achieves both small size and adequate hardness for handling, while the enteric coating ensures the acid is released only in the intestinal tract, maintaining pharmaceutical performance
3Reliability
If pimobendan is administered in forms that ensure adequate dosage strength, then therapeutic effectiveness is improved, but the formulation complexity and manufacturing difficulty increase
Solution Approach 1:
The patent applies preliminary action by pre-coating the citric acid particles with an enteric coating material before final tablet formulation. This preliminary step simplifies the overall manufacturing process by ensuring pH-dependent release characteristics are built into the core material, eliminating the need for complex post-formulation pH control mechanisms
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 ensures immediate release of pimobendan, improves dosing accuracy, and enhances compliance by reducing tablet size and hardness, allowing voluntary acceptance by animals and improved safety profiles for long-term treatment.
Implementation Method 1
Pimobendan is characterized by a low solubility in aqueous media and a very highly pH-dependent solubility. Depending on the buffer system used, about 100 to 300 mg/liter dissolve at a pH between 1 and 3, but at pH 5 only about 1 mg/liter will dissolve in water.
Implementation Method 2
The strongly fluctuating blood concentrations are said to be prevented by the acid microsphere, which is caused by the dissolving rate of citric acid, formed around the pimobendan particles. Said microsphere is always acidic and ensures a reliable, practically pH-independent dissolution and absorption of pimobendan.
Implementation Method 3
a process for preparation of solid formulations comprising the following steps: a) mixing pimobendan or a pharmaceutically acceptable salt thereof or crystalline forms thereof, a first part of a disintegrant, malic acid, at least one diluent, a flavoring agent, optionally at least one glidant, b) wet granulating the blend obtained in step a) with at least one binder and water, c) drying the obtained granules and optionally milling, d) mixing the dried granules obtained in step c) with a second part of the disintegrant, e) mixing at least one lubricant, and at least one glidant to the granules obtained in step d), and f) optionally compressing the mixture obtained in step d) to form a tablet.
Data Source
Figure 1
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AI summary
The invention relates to oral pharmaceutical compositions comprising pimobendan pharmaceutically active compound. It also relates to a method for preparing the same uses thereof.