The present study was aimed at the development of a redispersible multi-dose suspension based on coated microparticles to ensure easy swallowing and sustained release of metoprolol succinate. To provide sustained release of metoprolol succinate, the microparticles were prepared by drug loading and Eudragit NM coating in a fluid-bed coater. Compositions of the liquid suspension vehicle were selected to reduce solubility of metoprolol succinate. The effect of vehicle composition and suspension storage time at RT on drug leaching into the suspension vehicle and on the drug release profile were investigated. The approach allowed a redispersible multi-dose suspension of metoprolol microparticles which, after one month storage, displayed negligible drug leaching into the suspension vehicle and a sustained release profile comparable to the profile before storage.

1. Development of multi-dose oral sustained
release suspensions for older patients
with dysphagia
Kavil Patel1, Valentyn Mohylyuk1, Darragh Murnane1 2, Craig Richardson2 3, Fang Liu1 2
1 Department of Clinical and Pharmaceutical Sciences, University of Hertfordshire, Hatfield, UK
2 Fluid Pharma Ltd., Leeds Innovation Centre, 103 Clarendon Road, Leeds, LS2 9DF, UK
3 IP Group plc, The Walbrook Building, 25 Walbrook, London, UK
.
Most oral dosage forms such as tablets and capsules are unsuitable for older people
with swallowing difficulties. Capsules opening and tablet crushing are commonly
used to overcome this problem. In addition to safety and legal concerns, this
approach cannot be applied to sustained products because of the loss of their
functionality, consequently causing dose dumping, undesirable side effects and
even toxicity. The number of appropriate medicines for older patients with
swallowing difficulties is therefore limited because of the absence of appropriate
oral dosage forms. One of the most appropriate forms of medicines for patients
with swallowing difficulties are liquid formulations [1]. The objective of this study
was to develop a stable, redispersible multi-dose liquid suspensions based on
sustained release microparticles to facilitate swallowing in older patients with
dysphagia.
Metoprolol succinate drug loaded and sustained release film-coated microparticles
were prepared in a fluid-bed coater using microcrystalline cellulose (MCC) cores
(Cellets 90, Pharmatrans-Sanaq Pharmaceuticals AG, Switzerland).
Oral liquid suspension vehicles were prepared by dissolving vehicle 1 in deionised
water and mixing with vehicle 2. Metoprolol succinate (MS) solubility in water and
suspension vehicles was determined using shake-flask method after 72 hours at
room temperature.
Suspensions were prepared by adding the sustained release microparticles to
different mixture of vehicles to obtain an appropriate dose. Drug leakage from the
coated microparticles in the suspension vehicle (Bottle-test [2]) was carried out
during shelf storage at room temperature for one month. Dissolution tests of the
microparticles before and after storage were performed using USP II method
(50 rpm) in 500 ml of PBS pH 6.8. UV-absorption was measured at 274 nm.
The solubility of MS in the suspension vehicle significantly reduced with
increasing concentration of vehicles 1 and/or 2 (fig 2) in comparison to its
water solubility (191.7 mg/ml).
Figure 2: Effect of vehicle composition on the solubility of MS.
Redispersible multi-dose suspensions based on coated metoprolol succinate
sustained-release microparticles were developed. After one month storage at
room temperature, there was negligible leakage of drug into any of the vehicle
compositions tested and, regardless of vehicle choice, the sustained release
profile of metoprolol succinate did not significantly change upon storage.
1. Liu, F., Ghaffur, A., Bains, J. and Hamdy, S., 2016. Acceptability of oral solid medicines in older
adults with and without dysphagia: a nested pilot validation questionnaire based observational
study. Int J Pharm., 512, 374-381.
2. Dashevskiy, A., Mohylyuk, V., Ahmed, A.R., Kolter, K., Guth, F., Bodmeier, R., 2017. Micropellets
coated with Kollicoat® Smartseal 30D for taste masking in liquid oral dosage forms. Drug Dev Ind
Pharm, 43, 1548-1556
Introduction and Aims
Methods
Results & Discussion
References
After one month storage of MS microparticles in selected suspension vehicles,
the MS leakage from microparticles in the liquid vehicle did not exceed 1.7 %
of dose (table 1).
Characteristics
Vehicle 1/ Vehicle 2/ Water a
50/30/20 20/50/30 30/45/25
MS solubility, mg/ml (SD) 12.3 (0.3) 11.5 (0.2) 11.0 (0.1)
MS leakage after 1 month
storage, % of dose
1.7 1.3 1.6
Table 1. Characteristics of chosen vehicles for suspension.
a weight proportion of ingredients (%/%/%)
The dissolution profiles after one month of suspension storage in different
vehicles were similar to initial profile (similarity factor > 62% for all profiles).
Figure 3. Effect of vehicle composition and one month storage on the dissolution of
MS from microparticle suspension (n=6, SD<3%).
Conclusion
Figure 1:
Left: Particle size distribution of starting MCC cores vs final drug loaded and polymer
coated particles used in suspension formulation.
Right: SEM image showing cross section of microparticle with clear illustration of the
core, drug layer and polymer layer.
Sustained release microparticles were produced using starting cores with particle
size D50 of 86.5 µm (measured using laser diffraction method), loaded with
metoprolol succinate (MS) and coated with sustained release polymer. The final
coated particles achieved a particle size distribution with D50 < 250 µm (fig 1). The
achieved yield of coated non-agglomerated particles was more than 95%.