James W. Ayres

Processing factors in development of solid solution formulation of itraconazole for enhancement of drug dissolution and bioavailability

This study investigated solid solutions of itraconazole, a water insoluble antifungal, for improved dissolution and improved bioavailability. Influence of processing factors on drug and carrier properties in solid solution and subsequently on drug dissolution behavior was also studied. An optimized solid solution formulation was compared with marketed product in healthy human subjects under fasted and fed conditions for bioequivalency. Polyethylene glycol (PEG) and drug were made into a solid solution at 120 degrees C. The cooled, solid solution was then ground into granules of different sizes. Solid solutions of lower drug concentration dissolved at a faster rate, and drug dissolution improved considerably with increasing molecular weight of PEG. Initial treatment of itraconazole with the wetting agent/cosolvent glycerol prior to making itraconazole into a solid solution improved drug dissolution, and also reduced the PEG amount required to dissolve drug to form solid solution. Addition of a polymer such as HPMC to the solid solution eliminated precipitation of drug following dissolution. As the granule size of the solid solution was reduced, precipitation of drug during dissolution became prominent. Equivalence of two formulations could not be shown for pharmacokinetic parameters C(max) and AUC, under both fasting and fed conditions.

Calcium Alginate Beads as Core Carriers of 5-Aminosalicylic Acid

The utilization of calcium alginate beads as core carriers for delayed dissolution followed by burst release as a potential method of intestinal site specific drug delivery was investigated. 5-Aminosalicylic acid was spray-coated on dried calcium alginate beads and then coated with different percentages of enteric coating polymer and/or sustained-release polymer. Beads coated with more than 6% (w/w) methacrylic copolymer plastisized with dibutyl sebacate and triethyl citrate resisted release in 2-hr acid fluid challenge and allowed immediate dissolution upon transfer to simulated intestinal fluid. With 6% (w/w) methacrylic copolymer on top of 4% (w/w) ethylcellulose polymer, the major portion of drug did not release in 2 hr of acid treatment or the next 3 hr of simulated intestinal fluid treatment. This dosage form provides the possibility to deliver drug to the lower intestinal tract with minimal early release, followed by sustained release in the colon.

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.

Gastrointestinal Transit of Nondisintegrating, Nonerodible Oral Dosage Forms in Pigs

Gastrointestinal (GI) transit data necessary as “baseline” or “control” information were collected using pigs as animal models preliminary to bioavailability studies of new sustained action formulations. Density and size effects of nondisintegrating dosage forms on GI transit were investigated. Initially, enteric-coated nondisintegrating magnesium hydroxide caplets (density, 1.5 g/ml; size, 19.6 × 9.5 mm; weight, 1.2 g) were utilized in seven pigs. Prolonged gastric residence (>5 days) occurred in every case for this dosage form. Therefore, nondisintegrating caplets of three densities (1.25, 1.45, and 2.3 g/ml) and three different sizes (large, 20 × 10 mm; medium, 10 × 10 mm; small, 5 × 10 mm) were studied in two more pigs. Roentgenography was used to visualize passage of caplets through the GI tract. Heidelberg pH capsules (size, 8 × 20 mm; density, 1.61 g/ml) were also used in this study. Total GI transit times range from 2 to 33 days for 22 administrations of these nondisintegrating dosage forms. Pigs are found to not be an appropriate model for evaluating bioavailability of nondisintegrating controlled-release dosage forms because total GI transit time (especially gastric transit) is much too long.

Drug Release from Spray Layered and Coated Drug-Containing Beads: Effects of pH and Comparison of Different Dissolution Methods

Based on dissolution profiles of three model drugs on spray layered beads with the same percentage of Aquacoat coating, it was concluded that in vitro dissolution of oral controlled-release formulations should be performed in both gastric and intestinal media for ionizable drugs. Ketoprofen (weak acid, pKa 4.8), nicardipine HCl (salt of weak organic base, pKa 8.6), and acetaminophen (very weak organic acid, pKa 9.7, not ionized at physiologic pH) provided different dissolution characteristics in enzyme-free simulated gastric fluid (pH 1.4) and enzyme-free simulated intestinal fluid (pH 7.4), indicating that the rate of drug release was pH dependent and related to drug ionization even though the solubility of the coating (ethylcellulose) is pH independent. In acidic media, ketoprofen release from the beads containing low-level coating (3%) was slower than that of nicardipine HCl, with the opposite holding true in basic media. Acetaminophen was released at approximately the same rate in both acidic and basic media. A comparison of drug release profiles for nicardipine HCl nude beads was also investigated among three different dissolution methods: USP dissolution apparatus I (basket method, 50 rpm), USP dissolution apparatus II (paddle method, 50 rpm), and USP dissolution apparatus III (Bio-Dis, Van-Kel Industries, 5 and 10 dpm). Release profiles obtained from all methods were similar, indicating that the three dissolution methods were comparable.

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...

Single dose bioavailability of acetaminophen following oral administration

Saliva acetaminophen concentrations were determined in 15 subjects after administration of 5 different doses of commercial acetaminophen tablets (325 mg, 500 mg, 1000 mg, 1500 mg and 2000 mg acetaminophen). Drug concentration-time profiles were best described by either a one- or two-compartment pharmacokinetic model, depending on the treatment and subject. Statistically significant (P < 0.05) differences in elimination rate and dose-corrected area under the curve were found among treatments (doses) suggestive of dose-dependent pharmacokinetics.

Bead Compacts. I. Effect of Compression on Maintenance of Polymer Coat Integrity in Multilayered Bead Formulations

Little information is available on the compactability of beads for oral sustained-release dosage forms. It is known that polymer-coated beads may fuse together to produce a non-disintegrating controlled-release matrix tablet when compressed. This study evaluates the effect of compression on beads with multiple layers of polymer and drug coat, and the effect of cushioning excipients and compaction pressure on drug release from compressed bead formulations. The multilayered beads consist of several alternating layers of acetaminophen (APAP) and polymer coats (Aquacoat) with an outer layer of mannitol as a cushioning excipient. Percent drug release versus time profiles showed that the release of drug decreases from noncompacted beads as the amount and number of coatings increases, with only 43% of drug released in 24 hr for coated beads with 10 layers. It was shown that the compacted multilayered beads will disintegrate in gastrointestinal fluids, providing a useful drug release pattern. It was shown that beads of drug prepared by any method can be spray-layered with excipients such as Avicel and mannitol. Spray-layering of the cushioning excipient onto beads can provide an effective way to circumvent segregation issues associated with mixing of the polymer-coated beads and powdered or spherical/nonspherical cushioning excipients. Spray layering of the cushioning excipient can also provide excellent flow properties of the final formulation as visually observed in our experiments. Triple-layered caplets (TLC) were also prepared with outer layers of Avicel PH-101 or polyethylene oxide (PEO), and a center layer of polymer-coated beads. For TLC, the polymer coating on the beads fractured, and nondisintegrating matrix formulations were obtained with both caplet formulations.

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.