Keith A. Parrott

Design and evaluation of an oral controlled release delivery system for melatonin in human subjects

Six human subjects were given an oral formulation designed to provide an immediate and controlled release of melatonin (MT). The controlled release formulation consisted of MT-loaded sugar beads coated with 20% Aquacoat®. A computer simulation program (MAXSIM®) was used to estimate the MT dose and ratio of immediate and controlled release MT based on average population pharmacokinetics of MT. When 0.5 mg of MT (immediate release portion of MT, 0.1 mg) was administered to four subjects, average peak plasma MT concentration was reached at about 600 pg/ml and maintained at about 100 pg/ml over 8 h. Observed peak plasma MT concentrations were 3-times greater than predicted by simulation. These results suggest that the MT dose, ratio of immediate release MT to controlled release MT, and the controlled release dosage form must all be considered in order to closely mimic the endogenous plasma MT concentration-time curve. Deconvolution and pharmacokinetic analysis suggested that less than 20% of the orally administered controlled release MT dose reached the systemic circulation from time 0 to 8 h. A good correlation was observed between plasma MT concentration and urinary excretion rate of 6-sulphatoxymelatonin (6-STMT), a major metabolite of MT. As plasma MT concentration increased, the urinary excretion rate of 6-STMT increased concomitantly. This suggests that the urinary excretion rate of 6-STMT may be used as an index of human plasma MT concentration.

Development of a Transdermal Delivery Device for Melatonin In Vitro Study

AbstractThe present study was undertaken to develop a transdermal delivery device for melatonin and to determine the effects of system design on the release of melatonin. Melatonin(MT) diffusion characteristics from 2 solvents through a series of ethylene vinyl acetate membranes with 4.5%, 9%, 19%, 28% vinyl acetate were characterized using vertical Franz® diffusion cells. The solvent used were 40% (v/v) propylene glycol (PG) and 40%(v/v) propylene glycol with 30%(w/v) 2-hydroxypropyl-β-cytrodextrin. The best release rate (Jss = 0.795 μg/h/cm2) was obtained from the 40% PG vehicle through the 28% vinyl acetate membrane. Melatonin diffusion through this membrane with an acrylate pressure sensitive adhesive (PSA) with and without MT loading was also studied. The data revealed an interaction between MT and the PSA in the systems with MT-loaded adhesive. A MT transdermal delivery device was constructed based on the above data. Effect of storage time (1 day, 2 days, and 3 days) on the developed device was also...

Solubility and stability of melatonin in propylene glycol and 2-hydroxypropyl-β-cyclodextrin vehicles

The physicochemical properties of melatonin (MT) in propylene glycol (PG) and 2-hydroxypropyl-β-cyclodextrin (2-HPβCD) vehicles were characterized. MT was endothermally decomposed as determined by differential scanning calorimetry (DSC). Melting point and heat of fusion obtained were 116.9±0.24°C and 7249±217 cal/mol, respectively. MT as received from a manufacture was very pure, at least 99.9%. The solubility of MT in PG solution increased slowly until reaching 40% PG and then steeply increased. Solubility of MT increased linearly as concentration of 2-HPβCD without PG increased (R2=0.993). MT solubility in the mixtures of PG and 2-HPβCD also increased linearly but was less than the sum of its solubility in 2-HPβCD and PG individually. The MT solubility was low in water, simulated gastric or intestinal fluid but the highest in the mixture of PG (40 v/v%) and 2-HPβCD (30 w/v%) although efficiency of MT solubilization in 2-HPβCD decreased as the concentration of PG increased. MT was degraded in a fashion of the first order kinetics (r2>0.90). MT was unstable in strong acidic solution (HCl−NaCl buffer, pH 1.4) but relatively stable in other pH values of 4∼10 at 70°C. In HCl−NaCl buffer, MT in 10% PG was more quickly degraded and then slowed down at a higher concentration. However, the degradation rate constant of MT in 2-HPβCD was not changed significantly when compared to the water. The current studies can be applied to the dosage formulations for the purpose of enhancing percutaneous absorption or bioavailability of MT.

Development and Characterization of an Oral Controlled-Release Delivery System for Melatonin

Sugar spheres loaded with melatonin (MT) were coated with Aquacoat@ to control the release rate of MT. Dissolution of MT was evaluated using the USP basket method. With 18-20 mesh beads, T,,, (time to release 50% of drug) for 5%, 10%. and 20% coatings was I0 min, 35 min, and 60 min, respectively. A desired release pattern over 8 hours was obtained with 20% coating on 8-10 mesh beads. T,,, for 5%, lo%, and 20% coatings was about I, 2, and 4 hours, respectively. MT in 20% coated beads was quite stable during storage at room temperature with less than 5% MT degraded during 6 months of storage. Dissolution proBles from 8-10 mesh beads with a 20% coating were unchanged after 6 months of storage at room temperature, Administration of the dosage form to human subjects maintained MT plasma concentrations over 100 pghl for approximately 8 hours.

Percutaneous absorption and model membrane variations of melatonin in aqueous-based propylene glycol and 2-hydroxypropyl-β-cyclodextrin vehicles

Percutaneous absorption and model membrane variations of melatonin (MT) in aqueous-based propylene glycol and 2-hydroxypropyl-β-cyclodextrin vehicles were investigated. The excised hairless mouse skin (HMS) and two synthetic ethylene vinyl acetate (EVA) and microporous polyethylene (MPE) were selected as a model membrane. The solubility of MT was determined by phase equilibrium study. The vertical Franz® type cell was used for diffusion study. The concentration of MT was determined using reverse phase HPLC system. The MT solubility was the highest in a mixture of PG and 2-HPβCD. The percutaneous absorption of MT through excised HMS increased as the solubility increased. However, the permeability coefficient decreased and then slightly increased in a mixture of PG and 2-HPβCD. On the other hand, both flux and permeability coefficient through EVA membrane decreased as the solubility increased. No MT was detected over 12 h after starting diffusion through MPE membrane. The flux of MT was dependent on the type of membrane selected. Flux of MT was greatest in excised HMS followed by EVA and MPE membrane. Flux of MT through EVA membrane was 5}20 times lower when compared to excised HMS. Interestingly, volumes of donor phase when MPE membrane was used, significantly increased during the study period. The HMS might be applicable to expect plasma concentration of MT in human subjects based on flux and pharmacokinetic parameters as studied previously. The current studies may be applied to deliver MT transdermally using aqueous-based vehicles and to fabricate MT dosage forms.

Vitamin B-6 status of children undergoing continous ambulatory peritoneal dialysis

Abstract The purpose of this study was to evaluate the vitamin B-6 status of children undergoing continuous ambulatory peritoneal dialysis (CAPD) and to determine the renal and peritoneal clearance of vitamin B-6 in these children. Eight children, mean age 12 years, were included in the first study. Urine, dialysate and plasma were analyzed for total vitamin B-6 and pyridoxal 5′-phosphate (PLP). Dialysate total protein and serum alkaline phosphatase were also measured and a three day dietary record was obtained. Plasma PLP was measured in six subjects one year following the first study after they had been receiving daily pyridoxine supplements for one year. Mean plasma total vitamin B-6 and PLP were 304 and 25.5 nM, respectively, in the first study. The mean ratio of plasma PLP/total vitamin B-6 was 0.146. Mean plasma PLP in supplemented subjects was 60.4nM. Renal and dialysate clearance of vitamin B-6 was 0.41 and 0.90 mls/min, respectively. Mean dietary intake of vitamin B-6 was 59% of the RDA. CAPD treated children appear to be deficient in vitamin B-6 although dialysate losses are minimal. Pyridoxine supplements of at least 2mg/day are necessary to increase plasma PLP to normal concentrations in these children.

Batch variation and pharmacokinetics of oral sustained release melatonin-loaded sugar spheres in human subjects

The three different batches of an oral sustained release melatonin (MT) delivery system were prepared by aqueous-based fluid-bed coating of the sugar spheres for the evaluation ofin vitro release characteristics and plasma concentration profiles in human subjects. The MT contents in 20% coated sugar spheres of three batches (B1, B2 and B3) were 3.3±0.08, 2.4±0.1 and 2.5±0.13 mg per gram of coated sugar spheres, respectively. The release profiles of three different batches had a very similar fashion. However, the release half-lives (T50%) of MT from B1, B2 and B3 was 3.70±0.2, 5.2±0.2 and 4.9±0.07h, respectively. Plasma concentration profiles of sustained release 0.2mg melatonin-loaded sugar spheres containing 10% immediate release melatonin in gelatin capsules (B1 and B2) were then evaluated in human subjects. Thein vivo plasma concentration profiles of the two batches (B1 and B2) were very similar each other and located between the physiological endogenous ranges. The time to reach the peak concentration (Tmax) was more advanced in case of B1 when compared to B2. However, there was no statistically significant difference in the maximum concentration (Cmax) and the area under the curve (AUC) between B1 and B2. The AUC of melatonin-loaded sugar spheres containing 10% and 20% immediate release MT in human subjects had a good linearity between dose and AUC, regardless of the fraction of immediate release MT, indicating the first order elimination process of MT within these doses. The current oral sustained release MT delivery system may be utilized to treat circadian rhythm disorders if it is proven to be more clinically useful when compared to immediate release MT.

Determination of propranolol in peritoneal dialysis fluid by high-performance liquid chromatography without extraction

A rapid, sensitive method for the high-performance liquid chromatographic determination of propranolol in peritoneal dialysis fluid is described. An extraction step is replaced by the use of a C18 Sep-Pak cartridge for sample preparation. The procedure offers an acceptable alternative to sample extraction and will allow for pharmacokinetic studies of propranolol in patients undergoing peritoneal dialysis for chronic renal failure.