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

Percutaneous absorption and model membrane variations of melatonin (MT) in aqueous-based propylene glycol and 2-hydroxypropyl-beta-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-HP beta CD. 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-HP beta CD. 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.

Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: a crossover study with melatonin.

The effect of oral controlled-release (CR), oral transmucosal (buccal; TMD) and transdermal (TDD) drug delivery systems on plasma concentrations of melatonin (MT) and its principal metabolite in human subjects using a crossover, single dose design was evaluated. Twelve adult male volunteers participated in the study and received all three dosage forms on three separate occasions. All patch dosage forms were removed after 10 h of wear. Plasma concentrations of the parent drug and its metabolite, 6-sulfatoxymelatonin (MT6s) were measured by radioimmunoassay. Between-subject plasma concentrations of MT were very variable following both oral CR and TDD. Use of the oral CR system gave plasma MT profiles in some subjects that were initially similar to physiological levels, but then differed substantially from physiological in the rate of MT offset; in a few subjects, plasma MT levels remained consistently much below normal nocturnal physiological levels. Also, the ratio of metabolite to parent drug by the oral CR route was many times greater than physiological. TDD resulted in a significant delay in systemic drug levels and a gradual decline in drug delivery after patch removal, possibly due to deposition of melatonin in the skin. TDD failed to simulate the physiological plasma profile of MT (rapid achievement of steady-state blood levels and rapid decline after removal of the patch; i.e., so-called "square-wave" profile). TMD provided prompt systemic drug levels with less variability than oral CR or TDD delivery. Also, plasma MT levels fell promptly and rapidly after removal of the patch. No indication of mucosal deposition was observed. TMD was able to mimic the physiological plasma profiles of both MT and its principal metabolite.

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 (T(50%)) 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 (T(max)) was more advanced in case of B1 when compared to B2. However, there was no statistically significant difference in the maximum concentration (C(max)) 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.

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

The physicochemical properties of melatonin (MT) in propylene glycol (PG) and 2-hydroxypropyl-beta-cyclodextrin (2-HPbetaCD) 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 degrees 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-HPbetaCD without PG increased (R(2)=0.993). MT solubility in the mixtures of PG and 2-HPbetaCD also increased linearly but was less than the sum of its solubility in 2-HPbetaCD 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-HPbetaCD (30 w/v%) although efficiency of MT solubilization in 2-HPbetaCD decreased as the concentration of PG increased. MT was degraded in a fashion of the first order kinetics (r(2)>0.90). MT was unstable in strong acidic solution (HCl-NaCl buffer, pH 1.4) but relatively stable in other pH values of 4 approximately 10 at 70 degrees 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-HPbetaCD 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.

Preliminary evaluation of transdermal delivery of melatonin in human subjects.

A transdermal delivery device (TDD)1 was applied to four human subjects to investigate whether melatonin (MT) could penetrate through human skin. The TDD (total surface area of 3.80 cm2) was applied to the forearm of each subject. Plasma MT concentrations increased above baseline in approximately 2-4 hours, although steady state was not achieved in the 8-hour study period. Intersubject variation of plasma MT among four subjects was noted. Urinary excretion of 6-sulphatoxymelatonin (6-STMT), a major metabolite of MT in humans, increased as plasma MT concentrations increased. Cumulative amounts of urinary 6-STMT increased over a 6-hour period when the TDD was applied and were three times greater than in controls. The urinary excretion rate of 6-STMT was statistically correlated with plasma MT concentration among subjects (r2 = 0.77). These data suggest that the urinary excretion rate of 6-STMT can be used as an index of MT plasma concentrations in human subjects. Although an intersubject variability in both plasma MT concentration and urinary excretion rate of 6-STMT was noted, it was evident that MT can be delivered transdermally in human subjects.

Stability of levodopa in 5% dextrose injection at pH 5 or 6.

The stability of solutions of levodopa 1 mg/mL in 5% dextrose injection adjusted to pH 5 or 6 and stored at one of three temperatures was determined. Solutions were adjusted to pH 5 or 6 with sodium acetate injection or sodium phosphate injection, respectively. Three samples of solution adjusted to pH 5 were stored at each of three temperatures (4, 25, and 45 degrees C), and three samples of solution adjusted to pH 6 were stored at 25 degrees C. Samples were assayed for levodopa concentration by high-performance liquid chromatography at various times during the 21-day study period. All solutions maintained at least 90% of the initial concentration of levodopa for seven days. Discoloration of all solutions except those stored at 4 degrees C was noted at some point during the study period; solutions stored at 45 degrees C began to darken within 12 hours. The pH values of the solutions did not change during the study period. Under the conditions studied, solutions of levodopa 1 mg/mL in 5% dextrose injection adjusted to pH 5 or 6 are stable for seven days. Slight degradation of levodopa may cause a brownish-black discoloration of the admixtures.

Influence of cimetidine on the disposition of ibuprofen in the rat.

Ibuprofen is a non-steroidal anti-inflammatory agent which is extensively metabolized in both man and the rat. Cimetidine is a well known H2 antagonist which is known to inhibit microsomal enzyme drug metabolism. The influence of cimetidine on the disposition of ibuprofen was studied in Sprague-Dawley rats. Pretreatment with cimetidine was found to increase both the rate and extent of absorption of ibuprofen. Cimetidine treatment also inhibited acidification of gastric fluid. Pretreatment with SKF525A increased ibuprofen half-life but not absorption. Additional studies are necessary to determine the effect of cimetidine on the half-life and absorption of ibuprofen in man.

Eleven years of experience with capitation reimbursement for pharmacy services.

Pharmacy services encompass more than dispensing medications. However, traditional pharmacy reimbursement methods are based heavily on the dispensing of medications--i.e., on selling a commodity rather than providing a service. The capitation reimbursement method described provides the pharmacist with a means of reimbursement for professional services independent of the number of medications consumed by the patient. The pharmacist is thus free to encourage reductions in the consumption of medications without incurring an economic penalty. Such reductions are not only of potential benefit to the patient but can also reduce the workload of the nursing home staff. The feasibility of this capitation system is demonstrated by the successful pharmacy practice described.

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.

Stability of three oral liquid drug products repackaged in unit dose containers.

Stability of oral liquid forms of cimetidine hydrochloride, furosemide, and theophylline repackaged in polypropylene oral syringes and glass vials was assessed. Commercial preparations of each product were used; 2-ml quantities were placed in both types of container and stored at 4, 25, 44, 60, and 76 degrees C. Six samples from each container type at each temperature were tested at various times. Stability was defined as no greater than 10% loss of labeled potency. Assay was by high-performance liquid chromatography. All three drugs retained more than 90% of label claim in both types of containers after 180 days at 4 degrees C and 25 degrees C. For cimetidine hydrochloride and furosemide at these temperatures, there was no significant difference in concentration by container type; at the higher storage temperatures, the degradation rate in polypropylene syringes was significantly faster. For theophylline, loss of volume of 10% or greater occurred after 60 days at temperatures greater than 25 degrees C for both container types. Drug loss at higher temperatures was attributed to precipitation of theophylline out of the elixir rather than chemical degradation. Oral liquid cimetidine hydrochloride, furosemide, and theophylline repackaged in either polypropylene oral syringes or glass vials can be stored at 4 degrees C and 25 degrees C for 180 days with less than 10% loss of potency.

Drug waste in long-term care facilities: impact of drug distribution system.

The incidence and cost of drug waste in a long-term care facility (LTCF) were compared for a unit dose and a traditional (30-day card) distribution system. Drug records for 74 LTCF patients were reviewed retrospectively to determine the number of drugs ordered and doses dispensed during a four-month period via a unit dose distribution system. Based on the same drug orders, the number of doses that would have been dispensed with a 30-day card system was projected. The drug costs and wastage costs for the two distribution systems were compared. The mean number of drugs ordered per patient was 5.86. differences between the two systems, mean number of doses dispensed per order, and their average cost per drug order were not statistically significant (p less than 0.05). Of the total number of doses that would have been dispensed via the 30-day card system, 12.98% would have been wasted, representing 13.07% of the total drug costs. Because the unit dose system eliminates the drug wastage associated with a 30-day card system, it has a positive impact on LTCF drug costs.