H. W. Jun

Physicochemical and release studies of naproxen in poloxamer gels

The solubility of naproxen at pH 2 was significantly increased as a linear function of PF-127 concentration at three temperatures. Naproxen was highly entrapped by the micelles as indicated by large partition coefficients. The micellar solubilization was a spontaneous (ΔG 0). In the presence of PF-127, the release of naproxen across the membrane was significantly sustained at pH 2 and inversely proportional to the surfactant concentration. At pH 7, PF-127 had little effect on the membrane transport of naproxen. The release of naproxen from the PF-127 gel into isopropyl myristate was dependent on the medium pH. The highest release was observed at pH 6.3. The diffusion coefficients of naproxen were inversely proportional to drug loading and PF-127 concentration. The activation energy of 7.45 kcal/mol for the diffusion of naproxen in the gel was calculated using the Arrhenius equation.

Physicochemical studies of lidocaine–menthol binary systems for enhanced membrane transport

The melting properties of lidocaine and l-menthol binary systems were studied using differential scanning calorimetry (DSC). A eutectic mixture was obtained for the lidocaine:menthol ratio of 30:70 (w:w) with a eutectic point of 26 degrees C. The binary melt systems formed within a range of 30:70-50:50 (w:w) remained as homogeneous oils at ambient temperature. The solubilities of pure lidocaine and lidocaine from the binary melt systems were determined with and without propylene glycol in pH 8.0 phosphate buffer. Lidocaine from the melt systems was less soluble in the buffers due to the partition of lidocaine between the oil and aqueous phases. The addition of propylene glycol to the buffer significantly increased both the solubility and heat of solubilization of lidocaine. The permeation rates of lidocaine from the binary melt systems across shed snake-skin were concentration dependent and significantly higher than those from the reference solutions.

Pharmacokinetic and local tissue disposition studies of naproxen following topical and systemic administration in dogs and rats

The pharmacokinetic profiles of naproxen in blood and synovial fluid (SF) following topical and i.v. bolus administration in dogs, and the local tissue disposition of the drug following topical and oral administration in rats, were investigated to assess the feasibility of topical delivery of naproxen for local and systemic effects. The naproxen gel in poloxamer 407 (PF‐127) was applied on the stifle joint of dogs, and serum and synovial fluid samples were collected. For local tissue disposition studies, the naproxen gel was applied on the dorsal skin in rats, and blood, skin, and muscle samples were taken at 3, 6, and 12 h postdose after removing the residual gel from the skin. Steady state serum concentrations occurred at ∼20 h after topical doses and lasted for the next ∼30 h in dogs. Similar SF–serum concentration ratios of naproxen were found between i.v. (0·61±0·16) and topical (0·55±0·14) routes of administration. Following the i.v. dose, the half‐life of naproxen in SF (∼60 h) was significantly longer than that in serum (∼40 h). The bioavailability of naproxen in the topical gel was ∼2% of the applied dose in dogs. A large accumulation of drug in the epidermis, dermis, and muscle tissue beneath the gel application site was found in rats. Isopropyl myristate (IPM) significantly increased the systemic absorption as well as the concentrations of naproxen in the underlying dermis and muscle tissues, but exerted little effect on the disposition of naproxen in the epidermis.

Effectiveness and Mode of Action of Isopropyl Myristate as a Permeation Enhancer for Naproxen through Shed Snake Skin

The effectiveness and mode of action of isopropyl myristate (IPM) as an enhancer for the permeation of naproxen through shed snake skin have been investigated.

Pharmacokinetic Studies of Methotrexate in Plasma and Synovial Fluid Following IV Bolus and Topical Routes of Administration in Dogs

AbstractPurpose. The pharmacokinetic properties of methotrexate (MTX) in the plasma and synovial fluid (SF) after bolus IV and topical administration were studied in dogs to assess the feasibility of topical delivery of MTX for the treatment of rheumatoid arthritis. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation.

Determination of Trace Methotrexate and 7-OH-Methotrexate in Plasma by High-Performance Liquid Chromatog-Raphy with Fluorimetric Detection

Abstract A sensitive and reliable HPLC method consisting of a solid-phase extraction, post-column photoreaction of the analytes in a polyethylene tubing by UV lamp, and fluorimetric detection for the simultaneous determination of methotrexate (MTX) and 7-OH-methotrexate (7-OH-MTX) in plasma was developed. The linear relationships between the peak area and MTX (0.1 ng/ml-1000 ng/ml, r=0.9997) or 7-OH-MTX (6.25 ng/ml-400 ng/ml, r=0.9995) concentrations were obtained. The average coefficients of variation for the intraday and interday replications were less than 11% and the absolute recoveries were 96.8%-101.2% for MTX and 76.4%-86.7% for 7-OH-MTX for the calibration ranges used. The limit of detection for MTX in plasma was 0.05 ng/ml. This most sensitive HPLC method reported so far was used for the trace assay of plasma MTX concentrations in dogs following a topical application of MTX in gel.

Preparation and characterization of two-phase melt systems of lidocaine

The melting point of lidocaine was significantly lowered when mixed with thymol and/or aqueous ethanol. Mixtures of lidocaine and thymol at ratios within the range of 30:70-70:30 (w:w) became homogeneous oils at 25 degrees C. In a pH 9.2 carbonate buffer containing 25% ethanol, lidocaine (5%, w:w) also liquefied at 25 degrees C. The studies led to the development of novel two-phase melt systems of lidocaine (TMS) which consisted of a highly concentrated oil phase of lidocaine and an alcoholic aqueous phase. A compositional phase diagram showed that in aqueous dispersions of lidocaine, concurrent use of thymol and ethanol depressed the melting point of lidocaine more effectively than when they were used individually. Both thymol and aqueous ethanol were necessary as melting point depressing agents to achieve the highest possible lidocaine concentration of 87% (w:w) in the oil phase of a TMS at 25 degrees C. Containing an internal oil phase and an external aqueous phase at ambient temperature, such a TMS can be readily formulated into topical O/W cream after addition of proper surfactants and thickening agents. In an anesthetic activity test using mouse tail-flick model, a 5% lidocaine cream prepared was highly effective as shown by the prolonged latency time of the mice to a heat stimulus as compared with a placebo (P<0.05).

Fluorometric High Performance Liquid Chromatography for Quantitation of Naproxen in Serum

Abstract A simple, sensitive and reliable HPLC method for the determination of naproxen in serum is presented. Samples were prepared by a protein precipitation method using acetonitrile. A reversed-phase C-18 column was used with a mobile phase consisting of 47% acetonitrile and 53% pH 2.5 buffer solution. A fluorescence detection with excitation wavelength of 230 nm and emission wavelength of 370 nm provided high sensitivity and specificity with no interference from normal serum constituents. The limit of quantitation was 2.0 ng/ml with a CV of 10.6%. The standard plots were highly linear (r>0.999) over the range of 10.0–200.0 ng/ml. The average recovery was 97% and the CVs of inter- and intra-day variabilities were 2.0% and 1.2%, respectively, for the entire calibration range. The method was used for the measurement of the time course of naproxen in dog serum after administration of a topical gel.

Rapid Quantitation of Verapamil in Plasma by High-Performance Liquid Chromatography

Abstract A simple and sensitive liquid chromatographic assay procedure using a fluorescence detector for the quantitative determination of verapamil in plasma without extraction was developed. After precipitating the protein with acetonitrile, the resulting supernatant liquid was injected onto the column for analysis. Chromatographic separation was achieved on C18 reversed phase column and the eluting solvent was the isocratic mixture of methanol, acetonitrile and pH 3.0 glycine buffer (1:4:5). With this mobile phase the drug and its internal standard were well separated from the interference of the plasma sample. The average recovery of verapamil from 3 replicate samples of different concentration (100–600 ng/mL) were 95.5 ± 5.68%. The minimum amount of verapamil detectable by this method was 40 ng/mL of sample. The elimination half-life (β-phase) of this drug in rabbits was found to be 3.7 hours.

Determination of Carbamazepine in Uncoated and Film-Coated Tablets by HPLC with UV Detection

Abstract A simple and reliable method for the determination of carbamazepine in uncoated and film-coated tablets has been developed and validated by high-performance liquid chromatography with ibuprofen as the internal standard. The tablets were weighed and ground individually, and were extracted in methanol using method of sonification. The extract was diluted and purified using 0.45 µm membrane filter. Separation was achieved on an Econosphere C18 5µ analytical column with a mobile phase of 28:72 acetonitrile:sodium phosphate buffer. Detection was at UV 230 nm using a photodiode array detector. The mean retention times of carbamazepine and ibuprofen were 4.2 and 12.3 min, respectively. Peak height ratios were fit to a least squares linear regression for calculation of standard regression equation. The linear calibration range was from 5.0–25.0 µg/mL with the lower limit of detection (LLOD) of 18 ng/mL and the lower limit of quantitation (LLOQ) of 60 ng/mL. This simple and convenient method produced good linearity, precision, and accuracy and avoids using methylene chloride as the mobile phase. A modified USP method was also carried to analyze the drug content in the tablets. These results were compared statistically, and no difference was found between the new method and the modified USP method, while the new method is more convenient and is suitable for stability and dissolution studies of this drug.