How Technical Innovations May Help to Prevent Drug Shortages in Switzerland.

In this work, we investigated the technical feasibility of 'on-demand' production of selected drugs to cover their demand for a time window of 90 days. We focused on two sub-processes 'automated chemical synthesis' and 'formulation in micropellets'  to enable personalized dosing. The production of drugs 'on-demand' is challenging, important, but also attractive. Switzerland could thus gain access to an additional instrument for increasing resilience for supply-critical drugs. The biggest challenge in the case study presented here is the scalability of automated chemical synthesis and the application range of micropellet formulations.

Design, development and in-vitro evaluation of diclofenac taste-masked orodispersible tablet formulations.

CONTEXT: Fast onset of action is prerequisite for acute pain medication. A palatable orodispersible medicine of diclofenac providing rapid analgesic effect should improve patient compliance and treatment. OBJECTIVE: In the present study, diclofenac taste-masked orodispersible tablets (ODTs) with fast release characteristics were developed. Different taste-masking approaches and formulation concepts were screened in vitro for candidate selection. MATERIALS AND METHODS: Diclofenac was used as free acid. Five taste-masked microgranule formulations were prepared by wet granulation and/or coating processes, and compressed to ODTs. Citric acid (pH-modifying agent) and Eudragit® E PO (amino methacrylate copolymer) were used as taste-masking agents. Evaluation criteria were (i) disintegration time, (ii) processability and (iii) in-vitro dissolution profiles in simulated saliva (pH 7.4, 5 mL, 3 min) and compendial pH-change media (paddle, 50 rpm). The prototypes were compared to reference ODTs (without taste-masking). Most suitable ODT prototypes were selected and further evaluated for taste-masking efficiency using an electronic tongue. RESULTS AND DISCUSSION: In simulated saliva, the drug was slower released from the prototypes (between 1.1% and 15.5%) than from reference ODTs (23.7%). Less dissolved particles are thus expected in vivo for taste perception. Two ODT prototypes showed fast and complete drug release in phosphate buffer. The formulation providing the most efficient taste-masking was selected guided by electronic tongue data. CONCLUSION: A novel palatable and fast acting diclofenac ODT formulation was successfully developed. Formulation design, development and in-vitro evaluation used in this study may serve as rational approach for manufacturing taste-masked orodispersible dosage forms.

Design of biorelevant test setups for the prediction of diclofenac in vivo features after oral administration.

PURPOSE: Design of biorelevant test setups mimicking the physiological conditions experienced by drugs after oral administration along the passage through the mouth and the GI tract for the in vitro evaluation of diclofenac exhibiting multiple-peak phenomenon during absorption. METHODS: The biorelevant models simulated successively saliva (SSF, pH 6.2-6.75-7.4, 5 mL, 3 min), gastric (SGF-FaSSGF, pH 1.2-1.6, 50-250 mL, 30 min) and intestinal (FaSSIF, pH 6.8, 250 mL, 60 min) fluids. Applying these models, diclofenac free acid and its sodium/potassium salt were comparatively evaluated for dissolution and further characterized by HPLC, optical morphogranulometry, DSC and PXRD to elucidate peculiar behaviors. RESULTS: Diclofenac salts almost completely dissolved in SSF and showed a transitional dissolution pattern before complete precipitation in SGF/FaSSGF. This peculiar pattern correlated with simultaneous chemical modification and formation of agglomerates. With low dissolution in SSF and almost immediately complete precipitation, these behaviors were not observed with diclofenac free acid. Distinct diclofenac features were strongly determined by pH-modifications after oral administration. CONCLUSIONS: The multiple-peak phenomenon observed after administrating a solution, suspension or dispersible formulation of diclofenac salts are likely caused by drug precipitation and agglomeration in the stomach leading to irregular gastric-emptying. Diclofenac free acid may provide more reliable in vivo features.

Development of oral taste masked diclofenac formulations using a taste sensing system.

To achieve patient compliance, organoleptic aspects of drug substances play a key role in the development of oral pharmaceutical preparations. In this study, the ability of an electronic tongue to help in selecting a drug candidate and rationalize the development of oral taste masked formulations was evaluated. As drug, diclofenac, in the form of acid, sodium salt and potassium salt, was used. The taste sensing system Insent TS-5000Z was capable of differentiating diclofenac acid from its salts; and also distinguishing sodium and potassium salts eliciting similar taste modalities. Differences between qualities and intensities of sensor responses were mainly attributed to the different cations. Fewer taste and aftertaste stimuli were recorded for diclofenac acid. Based on this screening, the acid form was selected to formulate different diclofenac oral taste masked preparations further evaluated using electronic tongue data by comparing formulation prototypes against corresponding placebos. Output information demonstrated the ability of the taste sensors to detect and discriminate different formulation concepts and taste masking strategies. Comparative dissolution studies showed insufficient discrimination of formulation prototypes. Supported by these results, the electronic tongue proved to be a valuable additional tool for assessing and predicting the taste of active pharmaceutical ingredients in the early development stage.