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Aim Patients with classic congenital adrenal hyperplasia (CAH)have poor health outcomes. In the absence of a comprehensive observational study, this manuscript provides a model to esti-mate the lifetime disease burden of adults with classic CAH. Methods The model, built in Excel, comprises subdomains addressing the health consequences of CAH and synthesises evidence from clinical and epidemiological studies on health out-comes.Results The model estimates that adults with classic CAH will implement ‘sick day rules’ (doubling or tripling glucocorticoid and/or use of parenteral therapy) 171 times over their lifetime and attend hospital for adrenal crisis on 11 occasions. In a population of 1000, over 200 will die of a condition complicated by adrenal crisis resulting, on average, in a loss of 7 years of life.Patients with CAH may also suffer from excess CVD events.Treatment with glucocorticoids almost doubles the risk of bone fractures in patients with CAH compared to the general popula-tion, leading on average to an additional 08 fractures perpatient with CAH over their lifetime.Conclusions The disease burden model highlights gaps in evidence, particularly regarding intensity of care and adrenal crisis,and the relationship between control of CAH and risks of CVD, osteoporosis, diabetes and infertility. The model can be used for research on the impact of new clinical pathways and therapeutic interventions in terms of clinical events and cost.

Summary Objective Hydrocortisone via nasogastric (NG) tube is used in sick children with adrenal insufficiency; however, there is no licensed formulation for NG administration. Methods We investigated hydrocortisone recovery after passage through NG tubes in vitro for three formulations: liquid suspension, crushed tablets mixed with water, and hydrocortisone granules designed for oral administration to children. Cortisol was measured by LC‐MS/MS. Results Hydrocortisone content was variable and recovery low after preparation in syringe and prior to passage through NG tubes. For doses, 0.5 and 2.0 mg mean percentage recovery was as follows: liquid suspension 57% and 58%; crushed tablets 46% and 30%; and hydrocortisone granules 78% and 71%. Flushing the administering syringe increased recovery. Hydrocortisone recovery after passage with flushing through 6‐12Fr gauge NG tubes was variable: liquid suspension 61%‐92%, crushed tablets 40%‐174%, hydrocortisone granules 61%‐92%. Administration of hydrocortisone granules occluded 6 and 8Fr NG tubes; however, administration using a sampling needle to prevent granules being administered gave a recovery of 74%‐98%. Conclusions The administration of hydrocortisone through NG tubes is possible; however, current methods deliver a variable dose of hydrocortisone, generally less than that prescribed. Attention should be placed on the technique used to optimize drug delivery such as flushing of the administering syringe. Hydrocortisone granules block small NG tubes but behaved as well as the commonly used liquid suspension when prepared with a filtering needle that filters out granules.

SummaryObjective It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology. Design and Measurements Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population. Setting Field laboratories and clinical research facility. Results Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily ‘toothbrush’ regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg. Conclusion A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a ‘toothbrush’ regimen provides physiological cortisol exposure.

A new method of surface-selective laser sintering (SSLS) leads to the fabrication of three-dimensional (3D) composite scaffolds (spatial resolution ∼200 μm) that are both bioactive and biodegradable. Moreover, the scaffolds can have very precise dimensions and intricate structure. Conventionally, in selective laser sintering (SLS), the polymer absorbs infrared (λ=10.6 μm) radiation and this leads to a volumetric absorption by the whole polymer particle. In other words, each particle of polymer is completely melted and fuses to the next in order to form the desired morphology. In our experiments we have used near-infrared (λ=0.97 μm) laser radiation, which polymer particles do not absorb at all. To initiate the sintering process a small quantity (< 0.1 wt.-%) of carbon microparticles were homogeneously distributed on the surfaces of the polymer particles. Thus, the melting process was limited to only the surfaces of each particle. The carbon microparticles are strong absorbers of laser radiation, and this opens up the technique to a range of polymers that up till now could not be processed by laser sintering. More importantly, since the laser melts only the surfaces of the particles, delicate bioactive species trapped within each particle retain their activity throughout the processing. We have demonstrated the application of this technique by the incorporation of the enzyme ribonuclease A into particles of poly(d,l-lactic) acid (PLA) and the assembly of 3D matrices at three different laser intensities, using a 0.97 μm wavelength continuous wave (CW) diode laser.