In this paper we review cucurbit[n]urils (CB[n]), a relatively new family of macrocycles that has shown potential in improving drug delivery. Encapsulation of drugs within the homologues CB[6], CB[7], or CB[8] can impart enhanced chemical and physical stability, improve drug solubility, and control drug release. The formulation of CB[n] into a dosage form suitable for clinical use is a non‐trivial task, because the free macrocycle and its host‐drug complex generally exhibit pseudo‐polymorphism in the solid state. Despite this, cucurbiturils have been included in tablets for oral delivery and inserts for nasal delivery. Here we examine the potential use of cucurbiturils in drug delivery in the context of getting a new drug into clinical trials and discuss what further research is needed in this area.

The inclusion of the cardiovascular beta-blocker drug atenolol, the antidiabetic drug glibenclamide, the Alzheimer's NMDA glutamate receptor drug memantine and the analgesic/antipyretic drug paracetamol by cucurbit[7]uril (CB[7]) has been studied by (1)H nuclear magnetic resonance spectroscopy, electrospray ionisation mass spectrometry, molecular modelling, fluorescence displacement assays and differential scanning calorimetry. All four drugs form 1 : 1 host-guest complexes with CB[7], but the exchange kinetics and location of the binding is different for each drug. Atenolol is bound over the central phenyl ring with a binding constant of 4.2 x 10(4) M(-1), whereas glibenclamide is bound over the terminal cyclohexyl group with a binding constant of 1.7 x 10(5) M(-1), and memantine is totally bound within the CB[7] cavity. Paracetamol is bound in two locations, over the central phenyl ring and over the methyl group, with the CB[7] molecule shuttling quickly between the two sites. Inclusion by CB[7] was shown by differential scanning calorimetry to physically stabilise all four drugs, which has applications preventing drug degradation and improving drug processing and formulation.

Objectives-The aim of the study was to investigate the effect of microneedle (MN) treatment on the transdermal delivery of a model drug (rhodamine B, Rh B) encapsulated in polylactic-coglycolic acid (PLGA) nanoparticles (NPs) focusing on the MN characteristics and application variables. Methods-Gantrez®MNs were fabricated using laser-engineered silicone micro-mould templates. PLGA NPs were prepared using a modified emulsion-diffusion-evaporation method * Corresponding author. Conflict of interest:The Author(s) declare(s) that they have no conflicts of interest to disclose. Conclusions-This dual MN/NPs mediated approach offers potential for both the dermal and transdermal delivery of therapeutic agents with poor passive diffusion. Europe PMC Funders Group

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There is an urgent need to replace the injection currently used for low molecular weight heparin (LMWH) multi-dose therapy with a non-invasive delivery device. In this study, laser-engineered dissolving microneedle (DMN) arrays fabricated from aqueous blends of 15% w/w poly (methylvinylether co maleic anhydride) have been fabricated as a potential device for the active transdermal delivery of nadroparin calcium (NC) as a model LMWH. An array loading of 630 IU of NC was achieved without compromising the array mechanical strength or the drug bioactivity. Application of NC-DMNs to dermatomed human skin (DHS) using the single step “poke and release” approach allowed permeation of approximately 10.6 % of the total NC load over a 48 h-study period. The cumulative amount of NC that permeated DHS at 24 h and 48 h attained 12.28 ± 4.23 IU/cm2 and 164.84 ± 8.47 IU/cm2, respectively. Skin permeation of NC could be modulated by controlling the DMN array variables, such as MN length and array density as well as application force to meet various clinical requirements including adjustment for body mass and renal function. NC-loaded DMN offer potentials as a relatively low cost functional delivery system for the transdermal delivery of LMWH and other macromolecules.

The synthesis, processing, and solid state excipient interactions of cucurbit[6]uril (CB[6]) and its formulation into oral tablets has been examined using a range of physical chemistry techniques. Rapid precipitation from HCl by the addition of water yields microcrystalline CB[6] with smaller and more consistent particle size (30-165 μm) compared with the sieved CB[6] (50-540 μm) produced from large crystals grown by slow evaporation from HCl. The microcrystalline particles also contain fewer water molecules in the crystal compared with the sieved particles: 10 and 16% respectively. Microcrystalline CB[6] can be formulated into tablets suitable for oral delivery with a CB[6] content of 1-50% w/w, with the other excipients including lactose, talc, Avicel, magnesium stearate and Ac-Di-Sol. In the solid state microcrystalline CB[6] does not interact significantly with the talc, Ac-Di-Sol or Avicel, but significant interactions are observed when mixed or ground with either magnesium stearate or lactose, resulting in the lowering of the melting points of both excipients. This work represents the first study of the physical processing and solid state chemistry of CB[n]s for pharmaceutical formulation and represents an important development step in the use of CB[n]s as drug delivery vehicles.

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Single crystal and powder X-ray diffraction have been used to examine the host-guest complex of cucurbit [7]uril (CB [7]) and the model dinuclear platinum anticancer complex2+ (di-Pt, dpzm= 4,4¢-dipyrazolylmethane). The single crystal structure shows that the host-guest complex forms with the di-Pt dpzm ligand within the CB [7] cavity and with the platinum groups just beyond the macrocycle portals. Binding is stabilised through hydrophobic interactions and six hydrogen bonds between the platinum ammine ligands and the dpzm pyrazole amine to the CB [7] carbonyls. Each host-guest complex crystallises with two chloride counterions and 5.5 water molecules. The unit cell comprises four asymmetric units, each of which contains three crystallographically independent CB[7]-di-Pt moieties. X-Ray powder diffraction demonstrated structural consistency of the bulk crystals with a single polycrystalline phase that is identical with the single crystal structure. Finally, the effect of CB [7] encapsulation of the thermal stability of di-Pt was examined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). From the TGA experiments it was found that free CB [7] and the CB[7]-di-Pt complex lose 11 and 3.5% of their mass respectively, through the loss of water molecules, upon heating to 160• C. The DSC results showed that the free dpzm ligand melts between 186 and 199 • C, with a standard enthalpy of fusion of 27.92 kJ mol -1 . As a 2+ inorganic salt the metal complex does not melt but undergoes several decomposition events between 140 and 290• C. Encapsulation by CB [7] completely stabilises di-Pt with no decomposition of either the macrocycle or metal complex at temperatures up to 290 • C.