Dose Finding and Food Effect Studies of a Novel Abiraterone Acetate Formulation for Oral Suspension in Comparison to a Reference Formulation in Healthy Male Subjects.

Currently approved formulations of the androgen synthesis inhibitor abiraterone acetate (AA) consist of multiple tablets administered daily in a fasted state. Removing the food effect and switching to a suspension formulation is expected to improve the pharmacokinetic profile and facilitate drug administration for patients with late-stage prostate cancer. Two four-sequence, four-period randomized crossover investigations were undertaken to establish the pharmacokinetic profiles of single doses of commercially available Zytiga®, as the reference AA (R-AA), and a novel tablet for oral suspension (TOS). Four single doses of TOS (from 62.5 to 250 mg) were compared in study C01, and two single doses each of TOS (250 mg) and R-AA (1000 mg) were compared under fasted and fed (modified fasted for R-AA) conditions in C02. Plasma concentrations of abiraterone over time were measured, and pharmacokinetic parameters were calculated. Each doubling of the dose of TOS was associated with a greater than 3-fold increase in exposure. A single dose of TOS (250 mg) exhibited similar exposure over 24 h, whether given fasted (625 ng × h/mL) or fed (485 ng × h/mL). A single dose of TOS (250 mg) was associated with higher (fasted, p = 0.028) or equivalent exposure (fed) compared to 1000 mg R-AA fasted (532 ng × h/mL). Substantially higher exposures were seen with 1000 mg R-AA under modified fasted conditions compared to TOS, irrespective of prandial status (p < 0.001). TOS was generally safe and well tolerated in the study. A 250 mg dose of a novel AA formulation for oral suspension demonstrated bioequivalence to 1000 mg R-AA under fasted conditions. This novel TOS formulation also addresses some of the limitations of current AA treatment, including low bioavailability, high variability in systemic exposure and a large food effect. It may offer an alternative for patients with dysphagia or discomfort with swallowing large pills.

On-demand microfluidic control by micropatterned light irradiation of a photoresponsive hydrogel sheet.

Novel on-chip fluid control strategies, on-demand formation of arbitrary microchannels and parallel control of multiple microvalves were successfully demonstrated by means of computer-controlled micropatterned light irradiation of a photoresponsive hydrogel sheet.

Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect.

PURPOSE: Zytiga (abiraterone acetate, AA) is known to exhibit very low bioavailability and a significant positive food effect in men. The unfavorable pharmacokinetic properties are attributed to the inadequate and variable dissolution of the compound. Using a continuous flow precipitation technology, a novel AA formulation has been developed with improved solubility and dissolution characteristics. The current study was performed to evaluate the pharmacokinetics and safety of this novel formulation in healthy volunteers. METHODS: The study was conducted in 11 healthy men aged 47-57 years. All subjects received 3 consecutive single doses of the novel formulation of AA (100 and 200 mg in the fasted state and 200 mg in the fed state). Data were compared with pharmacokinetic and safety data reported for 1000 mg Zytiga, the marketed drug. RESULTS: The novel formulation of AA allows rapid absorption of the compound with t max values within 1 hour. Based on AUC values, a ~250 mg dose of the novel formulation is predicted to give the same exposure as 1000 mg Zytiga in the fasted state. The significant positive food effect was also eliminated; actually, a slight, but statistically significant negative food effect was observed. Variability of exposure was significantly reduced when compared to Zytiga. AA administered in the novel formulation was well tolerated with no IMP-related safety AEs reported. CONCLUSION: The novel formulation might allow a 75% dose reduction with significant reduction of inter-individual variability. The negative food effect observed requires further investigations; however, elimination of the significant positive food effect could be adequate to negate the restriction of a food label.

Development of an abiraterone acetate formulation with improved oral bioavailability guided by absorption modeling based on in vitro dissolution and permeability measurements.

Particle size reduction of drug crystals in the presence of surfactants (often called "top-down" production methods) is a standard approach used in the pharmaceutical industry to improve bioavailability of poorly soluble drugs. Based on the mathematical model used to predict the fraction dose absorbed this formulation approach is successful when dissolution rate is the main rate limiting factor of oral absorption. In case compound solubility is also a major factor this approach might not result in an adequate improvement in bioavailability. Abiraterone acetate is poorly water soluble which is believed to be responsible for its very low bioavailability in the fasted state and its significant positive food effect. In this work, we have successfully used in vitro dissolution, solubility and permeability measurements in biorelevant media to describe the dissolution characteristics of different abiraterone acetate formulations. Mathematical modeling of fraction dose absorbed indicated that reducing the particle size of the drug cannot be expected to result in significant improvement in bioavailability in the fasted state. In the fed state, the same formulation approach can result in a nearly complete absorption of the dose; thereby, further increasing the food effect. Using a "bottom-up" formulation method we improved both the dissolution rate and the apparent solubility of the compound. In beagle dog studies, this resulted in a ≫>10-fold increase in bioavailability in the fasted state when compared to the marketed drug and the elimination of the food effect. Calculated values of fraction dose absorbed were in agreement with the observed relative bioavailability values in beagle dogs.

Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method.

The oral bioavailability of Sirolimus is limited by poor dissolution of the compound in the gastrointestinal tract resulting in a low bioavailability and large inter-individual differences in blood levels. Several different formulation approaches were applied to overcome these disadvantageous pharmacokinetic properties including the marketed oral solution and a tablet form containing wet milled nanocrystals. These approaches deliver improved pharmacokinetics, yet, they share the characteristics of complex production method and composition. We have developed a nanostructured Sirolimus formulation prepared by the controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. We have shown that contrary to the batch production the process could be easily intensified and scaled up; apparently the uniformity of the precipitation is heavily dependent on the production parameters, most likely the mixing of the solvent and antisolvent. We compared the physicochemical and pharmacokinetic properties of the nanostructured formula with the marketed nanoformula. We found that our method produces particles in the size range of less than 100nm. The solid form redispersed instantaneously in water and in biorelevant media. Both the solid form and the redispersed colloid solution showed excellent stability even in accelerated test conditions. The oral administration of the nanostructured formula resulted in faster absorption, higher exposure and higher trough concentrations when compared to the marked form. These advantageous properties could allow the development of solid oral Sirolimus formulae with lower strength and gel based topical delivery systems.

Novel continuous flow technology for the development of a nanostructured aprepitant formulation with improved pharmacokinetic properties.

The oral bioavailability of Aprepitant is limited by poor dissolution of the compound in the gastrointestinal tract which is more prominent in the fasted state resulting in significant positive food effect. Due to the low aqueous solubility of the active substance the product development has been focused on decreasing the particle size of the active compound down to the submicron range in order to overcome this disadvantageous pharmacokinetic property. The marketed drug consisting of wet-milled nanocrystals exhibits significantly higher oral bioavailability in the fasted state and reduced food effect when compared to the unformulated compound. We have developed a novel process for the production of a nanostructured Aprepitant formulation in which the generation of the nanosized particles takes place at molecular level. The process relies on controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. The precise control of the production parameters (mixing geometry, flow rates, temperature, etc.) allows to tailor the physicochemical properties and biological performance of the active compound. We have prepared a novel nanostructured Aprepitant formulation using this method and compared its physicochemical and pharmacokinetic properties with the reference compound and the marketed nanoformula. We found that our method produces a stable amorphous solid form comprising novel nanostructured particles having a particle size of less than 100 nm with instantaneous redispersibility characteristics and improved apparent solubility and permeability. In vivo beagle dog pharmacokinetic studies showed that the novel formula exhibited greatly improved pharmacokinetic characteristics when compared to the reference compound, while serum blood concentrations for the nanostructured formula and the wet-milled formula were similar. The marked food effect observed for the reference compound was practically eliminated by our formulation method. These results indicate that the novel continuous flow precipitation technology is a suitable tool to prepare nanostructured formulations with similar, or even superior in vitro and in vivo characteristics when compared to the industrial standard milling technology.

Magnetodeformation effects and the swelling of ferrogels in a uniform magnetic field.

Magnetic field sensitive gels (ferrogels or magnetoelastic gels) are three-dimensional cross-linked networks of flexible polymers swollen by ferrofluids or magnetic fluids. We have studied the response of magnetic field sensitive polymer gels to an external magnetic field. Two phenomena were investigated in detail: deformation and swelling under a uniform magnetic field. Gel spheres containing magnetic particles distributed randomly in the gel matrix as well as pearl chain aggregates chemically fixed in the network were exposed to a static homogeneous magnetic field. It was found that the spatial distribution of the magnetic particles plays an essential role in the magnetodeformation effect. A weak effect was observed for gels containing randomly distributed magnetic particles. In response to the magnetic field induction, these gel spheres elongated along the field lines and were compressed in the perpendicular direction. No magnetodeformation was observed for gels containing aligned particles in the polymer matrix. The influence of an external magnetic field on the equilibrium swelling degree was also the subject of this study. Using thermodynamic arguments it was shown that a uniform external field may result in deswelling of the ferrogels at high field intensities.

Swelling kinetics of anisotropic filler loaded PDMS networks.

The kinetics of swelling of spherical poly(dimethyl siloxane) (PDMS) composite networks in cyclohexane has been studied. The PDMS composite gels contain magnetite and iron particles built in the network either in randomly distributed form or in chain-like structure. The composite gel becomes anisotropic in the terms of both, mechanical and swelling properties. As a consequence the swelling kinetics can be characterized by direction dependent relaxation time. The swelling kinetics of these samples has been compared to that of pure PDMS gels. It was found that Li-Tanaka theory can be applied to describe the swelling kinetics of PDMS network.