Chronotherapy based on modified-release hydrocortisone to restore the physiological cortisol diurnal rhythm.

In this inspirational note, we describe the development of an endocrine chronotherapy to restore the physiological rhythm of the essential adrenal stress hormone, cortisol. The challenges included demonstrating the circadian rhythm of the drug target, creating a drug formulation that replicated that rhythm and then proving benefit in clinical trials. The physiological cortisol circadian rhythm is well defined with cortisol levels high on waking and low on going to sleep. We experimented with different formulation technologies including modified-release tablets and multi-particulates to replicate the cortisol rhythm where absent through disease. We describe the development of Efmody®, a modified-release formulation of hydrocortisone, which replicates the cortisol diurnal rhythm and improves the disease control of congenital adrenal hyperplasia, the commonest hereditary form of adrenal insufficiency. This program shows it is possible, through modified-release technology, to treat chronic endocrine diseases with physiological replacement to preserve health for life.

An oral lipidic native testosterone formulation that is absorbed independent of food.

CONTEXT: There is no licensed oral native testosterone (NT) because of challenges in the formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels. OBJECTIVE: To develop an oral NT formulation. DESIGN AND METHODS: A lipid-based formulation of native testosterone filled into soft-gelatin capsules at 40 mg per capsule was designed with 2 years of stability at ambient temperature. Pharmacokinetic comparison studies of this oral lipidic NT formulation to oral TU were conducted in dogs and hypogonadal men. RESULTS: In dogs, 40 mg NT was well absorbed under fasted conditions whereas 40 mg TU required a high-fat meal: for NT, the mean fed/fasted AUC ratio was 1.63 and for TU 7.05. In hypogonadal men, fed and fasted NT had similar pharmacokinetics: Cmax mean 26.5 vs 30.4 nmol/L (769 vs 882 ng/dL), AUC0-10 h 87 vs 88.6 h nmol/L. NT (fed state) showed a testosterone AUC increase of 45% between 120 and 200 mg, and NT 200 mg gave a similar mean AUC0-10 h to TU 80 mg: 87 vs 64.8 h nmol/L. Serum TU levels were variable and on a molar basis were ~ten-fold higher than serum testosterone levels after TU 80 mg fed. The DHT: testosterone AUC0-10 h ratio was more physiological for NT than TU being 0.19 vs 0.36. There were no emerging safety concerns with NT. CONCLUSION: This novel oral lipidic native testosterone formulation has potential advantages over oral TU of dosing independently of food and a lower risk of supraphysiological DHT levels. Significance statement There is no licensed oral testosterone because of challenges in formulation, and the oral formulations of the ester, testosterone undecanoate, require a fatty meal for absorption and generate supraphysiological dihydrotestosterone levels. We have overcome the design challenges and formulated an oral native testosterone that can be taken with or without food and provides physiological levels of testosterone and dihydrotestosterone in hypogonadal men. This formulation, DITEST, has the potential advantage of being oral for patients who do not tolerate injections and less risk of adverse events that might theoretically be associated with elevated dihydrotestosterone levels. Future studies will need to define the dosing regimen for replacement in hypogonadal men.

Use of the Dynamic Gastric Model as a tool for investigating fed and fasted sensitivities of low polymer content hydrophilic matrix formulations.

The Dynamic Gastric Model (DGM) is an in-vitro system which aims to closely replicate the complex mixing, dynamic biochemical release and emptying patterns of the human stomach. In this study, the DGM was used to understand how the polymer content of hydrophilic matrices influences drug release in fasted and fed dissolution environments. Matrices containing a soluble model drug (caffeine) and between 10 and 30% HPMC 2208 (METHOCEL(®) K4M CR) were studied in the DGM under simulated fasted and fed conditions. The results were compared with compendial USP I and USP II dissolution tests. The USP I and II tests clearly discriminated between formulations containing different polymer levels, whereas the fasted DGM test bracketed drug release profiles into three groups and was not able to distinguish between some different formulations. DGM tests in the fed state showed that drug release was substantially influenced by the presence of a high fat meal. Under these conditions, there was a delay before initial drug release, and differences between matrices with different polymer contents were no longer clear. Matrices containing the typical amount of HPMC polymer (30% w/w) exhibited similar release rates under fed and fasted DGM conditions, but matrices with lower polymer contents exhibited more rapid drug release in the fasted state. In both the fasted and fed states erosion mechanisms appeared to dominate drug release in the DGM: most likely a consequence of the changing, cylindrical forces exerted during simulated antral cycling. This is in contrast to the USP tests in which diffusion played a significant role in the drug release process. This study is one of the first publications where a series of extended release (ER) formulations have been studied in the DGM. The technique appears to offer a useful tool to explore the potential sensitivity of ER formulations with respect to the gastric environment, especially the presence of food.

Development and testing in healthy adults of oral hydrocortisone granules with taste masking for the treatment of neonates and infants with adrenal insufficiency.

BACKGROUND: Treatment of neonates and infants with adrenal insufficiency is unsatisfactory because unlicensed hydrocortisone formulations are used. OBJECTIVES: The objectives were to survey current hydrocortisone prescribing practice and develop a novel hydrocortisone formulation, Infacort. METHODS: The use of hydrocortisone by European pediatric endocrinologists was surveyed. Based on this, an oral hydrocortisone granule formulation, Infacort, with taste masking was developed and evaluated in vitro and then in vivo in a phase I pharmacokinetic study. RESULTS: The survey showed that pediatricians use a variety of unlicensed compounded adult medications at doses of between 0.5 and 5 mg. Infacort was formulated with a taste-masking layer stable for at least 5 minutes in aqueous media and was produced in unit doses of 0.5, 1, 2, and 5 mg. Infacort 10 mg is the bioequivalent of a 10-mg hydrocortisone tablet (mean area under the curve from zero to infinity [AUC(0-inf)] ratio, 101%; 90% confidence interval, 96-107%). Mean cortisol maximum concentration (C(max)) and AUC(0-inf) values after administration of Infacort were linear with dose and dose proportional when adjusted for saturable plasma protein binding. Subjects rated Infacort as "not good or bad" for smell (86%), feel in the mouth (71%), and taste (79%). No serious adverse events were reported. CONCLUSIONS: This phase 1 study demonstrates that Infacort is safe, well tolerated, of neutral taste, bioequivalent to hydrocortisone licensed for adults, and shows dose proportionality with respect to cortisol exposure. Infacort is expected to facilitate optimization of hydrocortisone dosing in neonates and children with adrenal insufficiency; however, clinical studies will be required to demonstrate efficacy in this patient age group.

Investigation of critical core formulation and process parameters for osmotic pump oral drug delivery.

Push-pull osmotic pump (PPOP) tablets of a practically insoluble model drug were developed and the effect of various formulation and process parameters on tablet performance was evaluated in order to identify critical factors. The formulation factors such as the viscosity grade of polyethylene oxide as the primary polymer as well as the level and location of osmogen within the bilayer tablets led to a difference in performance of osmotic tablets and hence should be critically evaluated in the design of such dosage forms. Modification of granulation process, i.e., the granulating liquid composition or drying method of granules, did not impact the drug release from the osmotic tablets at the evaluated scale of this study. The influence of varying dose and aqueous solubility of other model drugs (i.e., theophylline, acetaminophen, and verapamil HCl) on the developed PPOP template was also investigated. Results showed that irrespective of the perceived complexity of development and manufacturing of osmotic pumps, the osmotic tablets in this study demonstrated a robust and yet flexible platform in accommodating different types of drug candidates, regardless of solubility, for the dose levels below 25% w/w of the pull layer formulation.

An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure.

OBJECTIVE: 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.

Modified-release hydrocortisone to provide circadian cortisol profiles.

CONTEXT: Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm. OBJECTIVES: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles. SETTING: The study was performed at a Clinical Research Facility. DESIGN AND METHODS: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen. RESULTS: The key variables in the physiological cortisol profile included: peak 15.5 microg/dl (95% reference range 11.7-20.6), acrophase 0832 h (95% confidence interval 0759-0905), nadir less than 2 microg/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (sem) maximum observed concentration of 16.6 (1.4) microg/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels. CONCLUSION: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol.

The distribution of water in degrading polyglycolide. Part II: magnetic resonance imaging and drug release.

This paper reports the use of magnetic resonance imaging (MRI) on polyglycolide disks to monitor the change in water ingress with degradation time. Very little response was measured before 13 days, but after this time, water began to penetrate the disks as fronts, starting from the sample surface and moving inwards towards the centre. These results provide more direct evidence in support of the four-stage degradation model for PGA outlined in previous literature, and in particular, that fairly sharp reaction-erosion fronts move in from the sample surface to the centre when the polymer is undergoing significant mass loss and water gain. A combination of MRI and drug release data suggest that fronts originate at the surface at about 7 (+/-2) days, and proceed at a rate of 0.033 (+/-0.002) mm/day. These results agree with results obtained from cumulative drug release profiles for different sample thicknesses presented in Part I. They support the hypothesis that drug releases quickly from the swollen regions behind the fronts where the polymer is open and porous, and that release finishes when the fronts meet in the centre of the sample.