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Graphical abstract, Medicine shortages have been spreading in European countries. In many cases, the unavailability of medicinal products has a substantial impact on the capability of National Healthcare Systems in ensuring the continuity of care. Shortages originate from multifactorial causes. In particular, they can be due to supply-related factors (e.g., manufacturing issues, regulatory issues, logistics, distribution) and demand-related ones (e.g., fluctuating drug demand, parallel market, tendering, price and reimbursement policies). However, some extraordinary geopolitical events (e.g., Brexit) may also affect medicines’ availability. The capability of European Regulatory Authorities and other stakeholders, which are involved in the pharmaceutical distribution chain and the healthcare assistance services, to define suitable problem-solving strategies has been limited for years by the fragmentation of the European regulatory framework, starting from the lack of a univocal definition of a medicine shortage. Only in 2019, the EMA and HMA joint task force released the first harmonized “shortage” definition in the European Economic Area (EEA) and guidance on public communication. This manuscript aims to review the current European regulatory framework on medicine shortages. To support the activities of regulators, manufacturers and other healthcare professionals, an algorithm was also proposed to be used as a harmonized procedure to determine the shortage/unavailability impact on public health and to rationalize the problem-solving strategies adopted in all different settings.

In a previous study, it was shown that the incorporation of poorly soluble drugs (BCS class II) in sugar glasses could largely increase the drug's dissolution rate [van Drooge, D.J., Hinrichs, W.L.J., Frijlink, H.W., 20041). Anomalous dissolution behaviour of tablets prepared from sugar glass-based solid dispersions. J. Control. Release 97, 441-452]. However, the application of this technology had little effect when high drug loads or fast dissolving sugars were applied due to uncontrolled crystallization of the drug in the near vicinity of the dissolving tablet. To solve this problem a surfactant, sodium lauryl sulphate (SLS), was incorporated in the sugar glass or physically mixed with it. Diazepam and fenofibrate were used as model drugs in this study. The dissolution behavior of tablets prepared from solid dispersions in which SLS was incorporated was strongly improved. Surprisingly, the dissolution rate of tablets prepared from physical mixtures of SLS and the solid dispersion was initially fast, but slowed down after about 10 min. The solid dispersions were characterized by DSC to explain this unexpected difference. These measurements revealed the existence of interaction of SLS with both the drug and the sugar in the solid dispersion when SLS was incorporated. It is hypothesized that due to this interaction, the dissolution of SLS was slowed down by which a high solubility of the drug in the near vicinity of the dissolving tablet is maintained during the whole dissolution process. Therefore, uncontrolled crystallization is effectively prevented. (c) 2007 Elsevier B.V. All rights reserved.

The molecular distribution in fully amorphous solid dispersions consisting of poly(vinylpyrrolidone) (PVP)-diazepam and inulin-diazepam was studied. One glass transition temperature (T-g), as determined by temperature modulated differential scanning calorimetry (TMDSC), was observed in PVP-diazepam solid dispersions prepared by fusion for all drug loads tested (10-80 wt.%). The T-g of these solid dispersions gradually changed with composition and decreased from 177 degrees C for pure PVP to 46 degrees C for diazepam. These observations indicate that diazepam was dispersed in PVP on a molecular level. However, in PVP-diazepam solid dispersions prepared by freeze drying, two T-g's were observed for drug loads above 35 wt.% indicating phase separation. One T-g indicated the presence of amorphous diazepam clusters, the other T-g was attributed to a PVP-rich phase in which diazepam was dispersed on a molecular level. With both the value of the latter T-g and the Delta C-p of the diazepam glass transition the concentrations of molecular dispersed diazepam could be calculated (27-35 wt.%). Both methods gave similar results. Water vapour sorption (DVS) experiments revealed that the PVP-matrix was hydrophobised by the incorporated diazepam. TMDSC and DVS results were used to estimate the size of diazepam clusters in freeze dried PVP-diazepam solid dispersions, which appeared to be in the nano-meter range. The inulin-diazepam solid dispersions prepared by spray freeze drying showed one T-g for drug loads up to 35 wt.% indicating homogeneous distribution on a molecular level. However, this T-g was independent of the drug load, which is unexpected because diazepam has a lower T-g than inulin (46 and 155 degrees C, respectively). For higher drug loads, a T-g of diazepam as well as a T-g of the inulin-fich phase was observed, indicating the formation of amorphous diazepam clusters. From the AC, of the diazepam glass transition the amount of molecularly dispersed diazepam was calculated (12-27 wt.%). In contrast to the PVP-diazepam solid dispersions, DVS-experiments revealed that inulin was not hydrophobised by diazepam, Consequently, the size of diazepam clusters could not be estimated. It was concluded that TMDSC enables characterization and quantification of the molecular distribution in amorphous solid dispersions. When the hygroscopicity of the carrier is reduced by the drug, DVS in combination with TMDSC can be used to estimate the size of amorphous drug clusters. (C) 2005 Elsevier B.V. All rights reserved.

The effect of carrier surface properties on drug particle detachment from carrier crystals during inhalation with a special test inhaler with basic air classifier has been studied for mixtures containing 0.4% budesonide. Carrier crystals were retained in the classifier during inhalation and subsequently examined for the amount of residual drug (carrier residue: CR). Carrier surface roughness and impurity were varied within the range of their appearance in standard grades of lactose (Pharmatose 80, 100, 110, 150 and 200 M) by making special sieve fractions. It was found that roughness and impurity, both per unit calculated surface area (CSA), tend to increase with increasing mean fraction diameter for the carrier. Drug re-distribution experiments with two different carrier sieve fractions with distinct mean diameters showed that the amount of drug per CSA (drug load) in the state of equilibrium is highest for the coarsest fraction. This seems to confirm that surface carrier irregularities are places where drug particles preferentially accumulate. However, a substantial increase in surface roughness and impurity appears to be necessary to cause only a minor increase in CR at an inspiratory flow rate of 30 l/min through a classifier. At 60 l/min, CR is practically independent of the carrier surface properties. From the difference in CR between 30 and 60 l/min, it has been concluded that particularly the highest adhesive forces (for the largest drug particles) in the mixture are increased when coarser carrier fractions (with higher rugosity) are used. Not only increased surface roughness and impurities may be responsible for an increase in the adhesive forces between drug and carrier particles when coarser carrier fractions are used, but also bulk properties may play a role. With increasing mean carrier diameter, inertial and frictional forces during mixing are increased too, resulting in higher press-on forces with which the drug particles are attached to carrier crystals and to each other.

In this study the possibility to deliver the acid-sensitive enzyme alkaline phosphatase (AP) from calf intestine (CIAP) to the intestinal system by oral administration was investigated. Tablets were prepared and in vitro evaluated. Final proof of concept studies were performed in rats. This acid labile enzyme is potentially useful in the treatment of sepsis, a serious condition during which endotoxins can migrate into the blood stream. The CIAP was freeze-dried with inulin and subsequently compacted into round biconvex tablets with a diameter of 4mm and a weight of 25-30mg per tablet. The tablets were coated with an enteric coating in order to ensure their survival in the stomach. In vitro evaluation of tablets containing alkaline phosphatase from bovine intestine (BIAP) was the first step in the development. It was found that tablets without enteric coating dissolved rapidly in 0.10M HCl with total loss of enzymatic activity of the alkaline phosphatase. Tablets that were coated were stable for at least 2h in 0.10M HCl, but dissolved rapidly when the pH was increased to 6.8. Furthermore, it was shown that the enzymatic activity of the released BIAP was fully preserved. The in vivo test clearly showed that the oral administration of enteric coated tablets resulted in the release of enzymatically active CIAP in the intestinal lumen of rats. The location of the enhanced enzymatic activity of AP in the intestines varied with the time that had passed between the administration of the tablets and the sacrificing of the rats. Also, the level of enzymatic activity increased with an increasing number of tablets that were administered. © 2003 Elsevier Science B.V. All rights reserved.