A View on Drug Development for Cancer Prevention.

Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention. SIGNIFICANCE: The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.

An investigation into the rheology of pharmaceutical inter-granular material bridges at high shear rates.

PURPOSE: This study was undertaken to investigate the rheological properties of inter-granular material bridges on the nano-scale when strained at high shear rates. MATERIALS AND METHODS: Atomic force microscopy (AFM) was used as a rheometer to measure the viscoelasticity of inter-granular material bridges for lactose:PVP K29/32 and lactose:PVP K90 granules, produced by wet granulation. RESULTS: The loss tangent (tan delta) and both the storage (G') and loss shear moduli (G'') of inter-granular material bridges were measured as a function of the probe-sample separation distance, oscillation frequency and relative humidity (RH). As the probe was withdrawn from the granule surface tan delta initially increased rapidly from zero to a plateau phase. G'' became increasingly dominant as the bridge was further extended and eventually exceeded G'. At high RH, capillary forces were foremost at bridge rupture, whereas at low RH elastic forces dominated. The effect of increasing frequency was to increase the effective elasticity of the bridge at high RH. CONCLUSIONS: AFM has been employed as a rheometer to investigate the nano-scale rheology of inter-granular material bridges. This novel method may be used to obtain a fundamental understanding how different binders, granulated with different diluent fillers, behave at high shear rates.

The surface characterisation and comparison of two potential sub-micron, sugar bulking excipients for use in low-dose, suspension formulations in metered dose inhalers.

PURPOSE: This study compares the surface characteristics and surface energetics of two potential bulking excipients, anhydrous sub-micron alpha-lactose and sub-micron sucrose, for use with low-dose, suspension formulations in pressurised metered dose inhalers (pMDIs). Both sub-micron bulking excipients are processed from parent materials (alpha-lactose monohydrate/alpha-lactose monohydrate and silk grade sucrose, respectively) so the surface characteristics of each material were determined and compared. Additionally, the surface energetics and adhesive interactions between each sub-micron bulking excipient and some chosen active pharmaceutical ingredients (APIs) used in pMDI formulations were also determined. From this data, it was possible to predict the potential degree of interaction between the APIs and each sub-micron bulking excipient, thus determining suitable API-excipient combinations for pMDI formulation optimisation. Salmon calcitonin was also investigated as a potential API due to the current interest in, and the potential low-dose requirements for, the pulmonary delivery of proteins. METHODS: The size and morphology of each sub-micron excipient (and parent materials) were determined using scanning electron microscopy (SEM) and the crystalline nature of each sub-micron excipient and parent material was assessed using X-ray diffraction (XRD). The surface chemistry of each sub-micron excipient was analysed using X-ray photoelectron spectroscopy (XPS). The surface energies of each sub-micron excipient, along with their respective parent materials and any intermediates, were determined using two techniques. The surface energies of these materials were determined via (a) single particle adhesive interactions using atomic force microscopy (AFM) and (b) 'bulk' material surface interactions using contact angle measurements (CA). From the CA data, it was possible to calculate the theoretical work of adhesion values for each API-excipient interaction using the surface component analysis (SCA). The Young's modulus for each sub-micron excipient and parent material was also determined using AFM. Finally, the adhesive interactions were determined between each sub-micron bulking excipient and five APIs (formoterol fumarate, salmeterol xinafoate, salbutamol sulphate, mometasone furoate and salmon calcitonin). RESULTS: Both sub-micron sucrose and anhydrous sub-micron alpha-lactose exhibited a lower surface free energy than their respective parent materials/intermediates. In addition, both AFM and CA surface energy measurements also showed that sub-micron sucrose has a higher surface energy than anhydrous sub-micron alpha-lactose. Theoretical work of adhesion values between anhydrous sub-micron alpha-lactose and each API are considerably lower than those observed between micronised alpha-lactose monohydrate and each API. Corresponding theoretical work of adhesion values between sub-micron sucrose and each API were almost identical to those observed between silk grade sucrose and each API. Young's modulus determination revealed that sub-micron sucrose has a greater crystal hardness/elasticity ratio than anhydrous sub-micron alpha-lactose. With the exception of salmon calcitonin, sub-micron sucrose showed larger adhesive interactions to the selected APIs than anhydrous sub-micron alpha-lactose. CONCLUSIONS: Anhydrous sub-micron alpha-lactose has been found to have lower adhesive interactions with a range of chosen, low-dose APIs compared to sub-micron sucrose. This could be related to the lower surface energy for anhydrous sub-micron alpha-lactose. Knowledge of the surface free energy and mechanical properties of potential sub-micron bulking excipients and API materials could provide useful information regarding the selection of suitable API-submicron bulking excipient combinations during the development and optimisation stages of suspension pMDI formulations.

Evaluation of crushed ticagrelor tablet doses: recovery following crushing and naso-gastric tube passage ex vivo.

BACKGROUND: Orally available ticagrelor in combination with low-dose aspirin (75-100 mg/day) is indicated for adult patients with acute coronary syndromes. However, patients with swallowing difficulties may be unable to consume the currently available 90-mg tablet. It is hypothesized that ticagrelor could be given to this patient cohort as a crushed dose administered either orally or via a naso-gastric (NG) tube. OBJECTIVES: To investigate the potential use of crushed ticagrelor tablets (90- and 180-mg doses) for oral dose or NG tube administration. METHODS: Ticagrelor tablets (90 or 180 mg [two 90-mg tablets]) were prepared to emulate oral and NG tube administration by similar methods. For the oral dose, ticagrelor tablets were crushed using a mortar and pestle and transferred to a dosing cup. 100 mL of water was added to the mortar, stirred, and the contents were transferred to the dosing cup and stirred to form a suspension. At this stage, where the suspension would normally be administered to a patient, it was collected for high performance liquid chromatography (HPLC) analysis. The mortar was then flushed with 100 mL of water, and the contents were again transferred to the dosing cup, stirred, and collected for HPLC analysis. For the NG dose, polyvinylchloride, polyurethane, and silicone size CH10 NG tubes were used. The tablets were crushed using a mortar and pestle, diluted with 50 mL of water, and stirred. At this stage, where the suspension would normally be administered to a patient through an NG tube using a syringe, it was collected for HPLC analysis. The mortar was then flushed with two additional 50 mL aliquots of water and the contents were passed through the NG tube. HPLC analysis examined the recoverability of ticagrelor in each of the dose suspensions and flushes and the stability of the suspension when held in a syringe for up to 2 h. RESULTS: One or two crushed 90-mg ticagrelor tablets, prepared for either oral or NG tube administration, delivers a mean dose of ≥97% of the original tablet. No degradation of the suspensions was detected after ticagrelor had been held in the syringe for up to 2 h. CONCLUSION: Although not an approved method of administration, these results suggest that ticagrelor tablets can be crushed and prepared for oral administration or for administration via an NG tube. From a clinical perspective, a syringe hold-time of up to 2 h should allow for enough time between preparation and administration (orally or via an NG tube) of the dispersed tablets to the patient. Future studies are required to test the effect of crushed dosing on pharmacokinetic and pharmacodynamic parameters.

Elucidation of the internal physical and chemical microstructure of pharmaceutical granules using X-ray micro-computed tomography, Raman microscopy and infrared spectroscopy.

X-ray micro-computed tomography (XMCT) was used in conjunction with confocal Raman mapping to measure the intra-granular pore size, binder volumes and to provide spatial and chemical maps of internal granular components in α-lactose monohydrate granules formulated with different molecular weights of polyvinyl pyrrolidone (PVP). Infrared spectroscopy was used to understand the molecular association of binder domains. Granules were prepared by high-shear aqueous granulation from α-lactose monohydrate and PVP K29/32 or K90. XMCT was used to visualise the granule microstructure, intra-granular binder distribution and measure intra-granular porosity, which was subsequently related to intrusion porosimetry measurements. Confocal Raman microscopy and infrared microscopy were employed to investigate the distribution of components within the granule and explore the nature of binder substrate interactions. XMCT data sets of internal granule microstructure provided values of residual porosity in the lactose:PVP K29/32 and lactose:PVP K90 granules of 32.41 ± 4.60% and 22.40 ± 0.03%, respectively. The binder volumes of the lactose:PVP K29/32 and lactose:PVP K90 granules were 2.98 ± 0.10% and 3.38 ± 0.07%, respectively, and were attributed to PVP-rich binder domains within the granule. Confocal Raman microscopy revealed anisotropic domains of PVP between 2 µm and 20 µm in size surrounded by larger particles of lactose, in both granule types. Raman data showed that PVP domains contained various amounts of lactose, whilst IR microscopy determined that the PVP was molecularly associated with lactose, rather than residual water. The work shows that XMCT can be applied to investigate granular microstructure and resolve the porosity and the excipient and binder volumes. Combining this technique with vibrational techniques provides further structural information and aids the interpretations of the XMCT images. When used complementarily, these techniques highlighted that porosity and binder volume were the most significant microstructural differences between the α-lactose monohydrate granules formulated with the different grades of PVP.