'Big Data' informed drug development: a case for acceptability.

Data, which help inform various stages of drug product development, are increasingly being collected using newer, more novel platforms, such as mobile applications, and analysed computationally as much larger 'Big Data' data sets, revealing patterns relating to human behaviour and interactions. Medicine acceptability gauges the ability and willingness of patients to take their dosage forms. It has become a crucial human component of drug product design. Vouching for the age appropriateness of medicinal products, acceptability related data are now expected by regulatory bodies. Shifting from traditional paper-based to electronic data-gathering platforms will allow the pharmaceutical industry to collect real-world, real-time, clinically relevant data, capable of informing current and future drug product development, reducing time and cost, and setting foundations for patient-centric drug product design.

New generalized poisson mixture model for bimodal count data with drug effect: An application to rodent brief-access taste aversion experiments.

Pharmacodynamic (PD) count data can exhibit bimodality and nonequidispersion complicating the inclusion of drug effect. The purpose of this study was to explore four different mixture distribution models for bimodal count data by including both drug effect and distribution truncation. An example dataset, which exhibited bimodal pattern, was from rodent brief-access taste aversion (BATA) experiments to assess the bitterness of ascending concentrations of an aversive tasting drug. The two generalized Poisson mixture models performed the best and was flexible to explain both under and overdispersion. A sigmoid maximum effect (Emax ) model with logistic transformation was introduced to link the drug effect to the data partition within each distribution. Predicted density-histogram plot is suggested as a model evaluation tool due to its capability to directly compare the model predicted density with the histogram from raw data. The modeling approach presented here could form a useful strategy for modeling similar count data types.

Demonstrating evidence of acceptability: the "catch-22" of pediatric formulation development.

Both researchers and practitioners have reached an influential period in the new era of developing pediatric medicines. Evolving regulatory reforms and guidance continue to serve as platforms steering research and development while distinctive opportunities and challenges in the field emerge. An advancing research need involves gaining a better understanding of end-user requirements and acceptability of formulations. This review considers solid oral forms to demonstrate the importance of such research to stakeholders in policy and practice.

The disintegration behaviour of capsules in fed subjects: a comparison of hypromellose (carrageenan) capsules and standard gelatin capsules.

Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) containing carrageenan as a gelling agent have been proposed as an alternative to conventional gelatin capsules for oral drug delivery. We have previously compared the disintegration of hypromellose(carrageenan) (Quali-V(®)) and gelatin capsules (Qualicaps) in fasted human subjects using the technique of gamma scintigraphy. This second study used the same technique with both fasted and fed human subjects. Size 0 capsules were filled with powder plugs made from lactose and did not contain croscarmellose as in the original study. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. The mean (±S.D.) disintegration time in the fasted state for the hypromellose(carrageenan) capsules was 8±2min and for gelatin 7±3min. These results were not statistically different from the data in the original study and show that the removal of the croscarmellose had no effect on the results. The mean (±S.D.) disintegration time in the fed state for the hypromellose(carrageenan) capsules was 16±5min and for the gelatin capsules was 12±4min. There was no statistical difference between the hypromellose(carrageenan) and gelatin capsules in either the fed or fasted state.

Assessment of liquid captopril formulations used in children.

OBJECTIVE: Unlicensed liquid captopril formulations are commonly used to treat children with heart disease. This study assessed the bioequivalence of two liquid preparations against a licensed tablet form. DESIGN: An open label, single dose, three-treatment, three-period, crossover trial. SETTING: Outpatient. PATIENTS: Healthy adult volunteers (n=18). INTERVENTIONS: Each subject was randomly assigned to one of six dosing sequences, and dosed with 25 mg captopril on each of three dosing visits separated by a washout of at least 14 days. Blood samples for pharmacokinetic analysis were taken at regular intervals (0 min to 10 h) post-dose. MAIN OUTCOME MEASURES: Bioequivalence of the formulations would be concluded if the 90% CI for the estimated ratio of the means of C(max) (maximum plasma concentrations) and area under curve(AUC) (extent of absorption) lay entirely within the range 0.8 to 1.25 RESULTS: Both liquid formulations failed the bioequivalence assessment with respect to C(max) and AUC. The 90% CI of the mean ratios of liquid/licensed tablet for both C(max) and AUC, fell outside the 0.8 to 1.25 limits. There was also considerable within-subject variability in C(max) (97.5%) and AUC (78.5%). CONCLUSIONS: Unlicensed captopril formulations are not bioequivalent to the licensed tablet form, or to each other, and so cannot be assumed to behave similarly in therapeutic use. Thus formulation substitution must be done with care and may require a period of increased monitoring of the patient. There is also significant within-subject variability in performance which has clinical implications with respect to titrating to an optimum therapeutic dose.

Administration of melatonin mixed with soft food and liquids for children with neurodevelopmental difficulties.

It is sometimes necessary for the contents of medication capsules to be mixed with certain foods and drinks because children are not always able to swallow the capsules. The compatibility and short-term stability (6h) of melatonin capsules mixed in a variety of liquids and foodstuffs (water, orange juice, semi-skimmed milk, strawberry yogurt, and strawberry jam) were analyzed for degradation. Extraction of melatonin from these common administration vehicles and an analytical assay for the drug and its potential degradation products were developed and validated. The results showed good recovery of melatonin from low- and high-strength capsules for all administration vehicles (between 89% minimum and 111% maximum). The drug was found to be stable in the common liquids and foods tested for up to 6 hours at room temperature (no degradation peak); hence it is unlikely to compromise the results of the Use of Melatonin in Children with Neurodevelopmental Disorders and Impaired Sleep trial.

Short term stability of pH-adjusted lidocaine-adrenaline epidural solution used for emergency caesarean section.

BACKGROUND: Lidocaine-bicarbonate-adrenaline mixtures are commonly used for epidural bolus doses for emergency caesarean section. Previous research has shown that adrenaline degrades completely 24 h after mixing. Anecdotal enquiries suggest that anaesthetists who use such mixtures commonly prepare the solution ahead of use, despite a lack of data about its stability between 0 and 24 h. The aim of this study was to monitor the degradation of adrenaline in the above mixture over 20 h. METHODS: 2 mL of sodium bicarbonate 8.4% was added to 20 mL of 2% lidocaine; 2 mL of this mixture was discarded and 0.1 mL of adrenaline 1:1000 added. The mixtures were stored in plastic syringes at 24 degrees C unprotected from light (n=3) or in the dark (n=3). Non-alkalinised controls were also prepared. Adrenaline and lidocaine were assayed by high performance liquid chromatography at 0, 2, 4, 6 and 20 h. RESULTS: In the bicarbonated mixture exposed to light, chemical degradation of adrenaline was fast at room temperature, only 73.0+/-3.6% of adrenaline remaining after 6h. In the dark, the stability of adrenaline improved and 95.8+/-3.6% remained after 6h. Negligible degradation occurred in the absence of bicarbonate in either condition. Lidocaine concentrations remained unchanged regardless of the storage conditions. CONCLUSIONS: This study suggests that preparation of pH-adjusted lidocaine-adrenaline mixtures in advance and prolonged storage in the light is inadvisable.

A scintigraphic investigation of the disintegration behaviour of capsules in fasting subjects: a comparison of hypromellose capsules containing carrageenan as a gelling agent and standard gelatin capsules.

Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) have been proposed as an alternative to conventional gelatin capsules for oral drug delivery; however, little is known about their in vivo behaviour. The aim of this study was to compare the disintegration of HPMC and gelatin capsules in fasted human subjects using the technique of gamma scintigraphy. HPMC capsules containing carrageenan as a gelling agent (QUALI-V(R), Qualicaps) and gelatin capsules (Qualicaps) of size 0 were filled with a lactose-based mixture. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. No differences in the oesophageal transit of the two types of capsules were noted, with the capsules arriving in the stomach in a matter of seconds. All the capsules disintegrated in the stomach. The mean (+/-S.D.) disintegration time for the HPMC capsules was 9+/-2min (range 6-11min). The corresponding mean time for the gelatin capsules was 7+/-4min (range 3-13min). These disintegration times were not significantly different (P=0.108, paired t-test). In conclusion, HPMC and gelatin capsules show rapid and comparable in vivo disintegration times in the fasted state. HPMC capsules containing carrageenan as a gelling agent therefore offer a practical alternative to gelatin capsules as an oral drug delivery carrier.

Physical and microbiological stability of an extemporaneous tacrolimus suspension for paediatric use.

OBJECTIVE: An extemporaneous suspension of tacrolimus for paediatric use has recently been developed but poor bioavailability and erratic plasma concentrations were observed during clinical use. It was not clear whether this was due to changes in the physical properties of the suspension during storage. The aim of this work was to investigate the physical and microbiological stability over the recommended 8-week shelf-life of this extemporaneous tacrolimus suspension. METHODS: Suspensions (0.5 mg/mL) were custom made by a special manufacturer under Good Manufacturing Practice conditions. The procedure involved mixing tacrolimus capsule contents into Ora Plus and Simple Syrup (1 : 1) using a mortar and pestle followed by an homogenization step. The particle sizes of the suspensions were measured using a MasterSizer. A light microscope equipped with polarizers was used to visualize any particle size changes or crystal growth. Viable bacterial and fungal contamination was assessed using standard colony count techniques on solid media. The suspensions were kept at 22-26 degrees C and evaluated weekly. RESULTS: The volume mean diameter d((4,3)) from laser diffraction did not change significantly. Light microscopy did not reveal any significant change in particle size or crystal growth. Contamination by viable and culturable micro-organisms could not be detected. CONCLUSION: The suspension was physically (particle size) and microbiologically stable during the 8-week study period suggesting other factors including poor dosing could be responsible for the pharmacokinetic variation observed during clinical use which warrants further investigation.

Colonic delivery of 4-aminosalicylic acid using amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsules.

BACKGROUND: 4-Aminosalicylic acid has the potential for use in the treatment of diseases of the colon. AIM: To assess the feasibility of delivering 4-aminosalicylic acid directly to the colon using a hydroxypropylmethylcellulose capsule coated with a mixture of amylose, a polysaccharide metabolized by bacterial enzymes in the colon, and ethylcellulose. METHODS: Seven healthy male volunteers received, on three separate occasions, an uncoated or amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsule containing 4-aminosalicylic acid Na (550 mg), or an intravenous injection of 4-aminosalicylic acid Na (135 mg). The capsules were radiolabelled with 99mTc to allow their positions in the gastrointestinal tract to be followed using a gamma camera. Plasma and urine samples were collected and assayed for 4-aminosalicylic acid and metabolite concentrations. RESULTS: The uncoated capsules broke down within 10 min in the stomach, allowing rapid and complete absorption of the drug. The coated capsules remained intact in the upper gastrointestinal tract, and had a median gastric emptying time of 61 min (interquartile range, 77 min) and a median colon arrival time of 363 min (interquartile range, 185 min). For the coated capsules, only the metabolite was detected in the plasma and/or urine after the capsules had reached the colon. CONCLUSIONS: The specific coating protected the drug until the capsule reached the colon, where 4-aminosalicylic acid was slowly released and absorbed. Thus, such a formulation has the potential for use in the treatment of inflammatory bowel disease.

Colonic delivery of sodium butyrate via oral route: acrylic coating design of pellets and in vivo evaluation in rats.

Few pharmaceutical studies, with the exception of those on rectal solutions, are described on short chain fatty acid (SCFA) formulations-especially for sodium butyrate, which is a colonocyte preferential substrate. Highly dosed butyrate pellets (90%) were prepared and their coating was designed for colonic delivery. In vivo determination (pH and transit time of pellets in rats) allowed to respectively choose the grade and thickness (resistance of 6 h) of the pH-dependent coating (Eudragi L+S, 1:1). The coated pellets were administered to naturally butyrate-deprived rats. The rats' colonic mucosa had the particularity to weakly express mitochondrial HMG-CoA synthase, an enzyme that responds to luminal butyrate. The results did not show early absorption of butyrate, but a probable cecal loss in the rat cecum as cecal residence time of the pellets was important and as pH was propitious for the coating hydrolysis. It seemed that butyrate, given daily for 7 days without the other main SCFA. was unable to induce the enzyme and/or that the dose (0.32 mmol/day) was insufficient.

Poloxamer 407 as a thermogelling and adhesive polymer for rectal administration of short-chain fatty acids.

OBJECTIVES: The purpose of the study was to gel a rectal solution of short-chain fatty acids to decrease the loss of active materials in the colonic lumen and thereby optimize their absorption. METHODS: Five thermogels were prepared with poloxamer 407 at concentrations ranging from 17% to 20%. Their viscosities were measured at room temperature and 37 degrees C, and their gelling temperatures were determined. The adhesive properties of each gel were assessed in vitro at 37 degrees C. Short-chain fatty acid release was studied using Guyot cells. RESULTS: From the threshold concentration of 17.5%, the solutions, Newtonian at room temperature (50-80 mPa x s), gelled at 37 degrees C. The higher the concentration, the higher the viscosity (1750 to 49,000 mPa x s), the lower the gelling temperature (27.6 degrees C to 23.4 degrees C), and the stronger the work of adhesion (2.2 to 4.5 mJ). Short-chain fatty acid release from the 18% polymer gel was decreased by 60% compared to the rectal solution. CONCLUSION: The 18% poloxamer 407 concentration provided a solution that was liquid at room temperature, that gelled at 37 degrees C, possessed adhesive properties, and controlled short-chain fatty acid release.

Gastrointestinal transit of pellets in rats: effect of size and density.

Gastrointestinal distribution kinetics of a large amount (0.5-1 g) of three types of non-disintegrating pellets which had the same size (S1, 710-1000 micrometers) but different densities (D1, 0.9 and D2, 1.5 g cm-3), or which had the same density (D1) but different diameters (S1 and S2, 1250-1600 micrometers) were examined in fed rats. The percentage of pellets remaining in the stomach, small gut, caecum and colon was measured at suitable intervals. Whatever the size of the pellets, the heavier the density, the longer the gastric emptying (2.1 h for D2-S1 instead of 1.3 h for D1-S1 and 0.7 h for D1-S2). The small gut transit time was not influenced by density but was slightly prolonged by size: 3.3 h for D1-S2 instead of 2.6 h for D1-S1 and D2-S1. Conversely, the gastrocolonic transit time was widely influenced by density (13.5 h for D2-S1) and somewhat by size (8.2 h for D1-S2 and 4.5 h for D1-S1). This delays were proportional to caecal residence time in the large, sacculated and derivated caecum of rats. In order to use the rat as an experimental model for pharmaceutical pellets, those results should have implication for the design of dosage forms, particularly those for controlled or timed release or those for targeted release at specific positions in the gastrointestinal tract.

Small-scale characterization of wet powder masses suitable for extrusion-spheronization.

The method of compresso-rheology with an Instron 5567 was used for flow assessment of wet powder mass in order to improve its formulation. In our experiments, the method was efficient for selection of the excipient (Avicel CL611) able to improve the extrusion behavior of the high-dose wet powder mass. The method also allowed the determination of the minima and maxima of the wetting agent volume necessary to identify the correct moisture content for extrusion (20%). The results were not discriminative for the choice of the Avicel CL611 amount in the formulae even if an average amount necessary to improve extrudability of the active ingredient could have been estimated at about 10%. Nevertheless, this method appeared to be a rapid and easy small-scale method for studying wet powder mass, cause only a few grams of solids are required, this rheometer should prove useful in formulation research.