Min-Hwa Lee

Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum.

Mucoadhesive liquid suppositories were prepared by adding mucoadhesive polymers (0.6%) to a formulation of thermally gelling suppositories that contained poloxamer 407 (15%), poloxamer 188 (15%) and propranolol HCl (2%). Hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carbopol, polycarbophil and sodium alginate were examined as mucoadhesive polymers. The characteristics of the suppositories differed depending on the choice of mucoadhesive polymer. For example, the gelation temperature was between 30 and 36 degrees C, the mucoadhesive force was between 430 and 5800 dyne/cm2, the apparent first-order release rate constant in phosphate buffer, pH 6.8, was between 0.399 and 0.271 h-1, the migration distance of the suppository in the rectum 4 h after administration was between 1 and 5 cm, and the bioavailability of propranolol was between 60.9 and 84.7%. Rectal bioavailability increased as the mucoadhesive force increased (r=0.984, p<0.0005), and the migration distance decreased (r=-0.951, p<0.005). No relationship was found between the bioavailability and the gelation temperature, drug release or irritation of the rectal mucosal membrane by the suppository. Therefore, retaining propranolol at the dosed site in the rectum by the addition of appropriate mucoadhesives to the formulation of liquid suppositories appears to be a very important factor in avoiding first-pass hepatic elimination and thereby increasing the bioavailability of the drug. Among the mucoadhesive polymers examined, sodium alginate and polycarbophil exhibited the largest mucoadhesive force and the smallest intrarectal migration resulting in the largest bioavailability of propranolol (84.7 and 82.3%, respectively). In contrast to other polymers, sodium alginate alone caused no irritation of the rectal mucosal membrane. Thus, poloxamer liquid suppositories containing sodium alginate appears to be a preferred formulation for drugs that are sensitive to extensive first-pass metabolism.

In vitro skin permeation of nicotine from proliposomes

Abstract The feasibility of proliposomes as a sustained transdermal dosage form was examined. Proliposomes containing varying amount of nicotine were prepared by a standard method using sorbitol and lecithin. The porous structure of sorbitol in the proliposomes was maintained, indicating that the majority of lecithin and nicotine is deposited within their porous matrix of the sorbitol particles. As a consequence, the flow properties of the proliposome particles was comparable to that of original sorbitol particles. Microscopic observation revealed that proliposomes are converted to liposomes almost completely within minutes following contact with water. It indicates that proliposomes may form liposomes by the sweat when they are applied on the skin under occlusive conditions in vivo. The size distribution of the reconstituted liposomes and nicotine release to pH 7.4 phosphate buffer from them were not significantly affected by the content of nicotine. The release pattern was apparently identical to the Exodus® patch, a commercially available transdermal nicotine formulation. We also studied in vitro permeation of nicotine across rat skin from proliposomes in a modified Keshary–Chien diffusion cell where the experimental set up simulates in vivo application of the proliposomes under an occlusive condition. The nicotine flux from proliposomes was initially retarded compared with that of nicotine powder. The flux from proliposomes appeared to remain constant throughout the experimental period compared with that of nicotine powder, indicating that nicotine may be delivered across the skin in a sustained manner at a constant rate from proliposomes. These results, therefore, indicate that sustained transdermal delivery of nicotine is feasible using proliposomal formulations if the formulations are topically applied under occlusive conditions.

Prolonged delivery of nicotine in rats via nasal administration of proliposomes

In order to achieve a prolonged delivery of nicotine to the systemic circulation, proliposomes containing nicotine base (NB-proliposomes) or nicotine hydrogen tartarate salt (NS-proliposomes) and a mixture of powdered nicotine hydrogen tartarate salt and sorbitol (1:9 mixture, MP) were administered intranasally to rats at a nicotine dose of 1 mg/kg. Proliposomes, lipid-sorbitol mixtures that form liposomes upon contact with water, were prepared according to previously established methods, and the mixture (MP) was prepared by mixing NS powder with sorbitol particles (105-350 micrometer in size). Nasal absorption of nicotine from these formulations was very rapid (i.e. less than 10 min was required to reach plasma peaks) and showed substantially sustained plasma nicotine levels compared to saline solutions of NB and NS, and previously reported nasal nicotine sprays. The AUC values from the proliposomes and MP were comparable to those from the saline solutions of NB and NS. However, the mean residence time (MRT) and plasma half-life (T(1/2beta)) of nicotine in the present study were much larger than those from the saline solutions. Thus, a prolonged delivery of nicotine to systemic circulation via the application of proliposomes or MP intranasally appears feasible. NB-proliposomes exhibited the best characteristics in terms of the area under the plasma concentration (AUC), MRT and T(1/2beta) of nicotine, which was followed by NS-proliposomes and MP. Retarded conversion of proliposomes and MP to liposomal emulsions and solution in the nasal cavity seems responsible, in part, for the sustained plasma nicotine concentrations, since the emulsions and solution yielded very short MRT and T(1/2beta) of nicotine. In addition, reduced metabolism to cotinine from the proliposomes and MP was apparently responsible for the sustained plasma nicotine levels. These dosage forms of nicotine appear to circumvent some of the shortcomings of transdermal patches (i.e. long T(max)) and nasal sprays (i.e. short T(1/2beta) and physicochemical instability).

Inverse targeting of drugs to reticuloendothelial system-rich organs by lipid microemulsion emulsified with poloxamer 338

Abstract Lipid microemulsions (LM) consisting of soybean oil and lecithin have been studied as a parenteral drug delivery system for site-specific delivery of non-water-soluble drugs. A major obstacle to targeting to non-RES organs or maintaining high concentrations of LM in vasculature is their rapid and extensive uptake by the RES in the liver and spleen. By replacing lecithin with hydrophilic poloxamer 338, it has been possible to avoid the normal deposition of LM in the liver and spleen (inverse targeting). Poloxamer 338-modified LM (PLM) containing ibuprofen octyl ester was intravenously administered to rats. Ibuprofen concentrations in the plasma and various organs were measured to elucidate the effect of inverse targeting to RES and targeting to other tissues in terms of the incorporated drug rather than the drug carrier. It was suggested that PLM can be exploited to direct lipophilic drugs in LM away from RES in the liver and spleen to other targeting tissues such as inflammatory tissues.

Simultaneous GC-MS determination of nicotine and cotinine in plasma for the pharmacokinetic characterization of nicotine in rats

A gas liquid chromatography/mass spectrometry assay method was developed for the simultaneous determination of nicotine and its major metabolite, cotinine, in rat plasma. Of particular interest was improving the low and variable extraction recovery for the parent drug and the metabolite. In addition, the feasibility of this assay method for pharmacokinetic studies of nicotine and cotinine after intravenous (i.v.), oral, and intraperitoneal (i.p.) administration of 1 mg kg(-1) of nicotine was tested. The low (30 and 48% for nicotine and cotinine, respectively) and variable (25 and 22% coefficient of variation for nicotine and cotinine, respectively) extraction recovery for nicotine and cotinine into dichloromethane was significantly improved by the addition of NaCl to the plasma. As a result, the recoveries for nicotine and cotinine were improved to 68 and 65%, respectively. The coefficient of variation was less than 10% in the 50-500 ng ml(-1) range and less than 16.58% at 10 ng ml(-1) for both nicotine and cotinine, indicating that the reproducibility of the assay was also improved by the extraction procedure. When injected intravenously at a dose of 1 mg kg(-1), the temporal profile of plasma concentration for nicotine followed a bi-exponential decline. Moment analysis revealed that pharmacokinetic parameters for nicotine (i.e. Cl, 46.30 ml min(-1) kg(-1); Vss, 2.77 1 kg(-1)) was similar to those reported in studies using 14C-nicotine. Absolute bioavailabilities of nicotine for i.p. and oral administration were 87.0 and 80.4%, respectively. The concentration of the metabolite increased up to 4 h to reach Cmax after i.p. and oral administrations and then declined slowly with time. These results indicate that this convenient analytical procedure is readily applicable to pharmacokinetic studies of nicotine and cotinine involving small laboratory animals with a sensitivity comparable with that reported for studies using 14C-nicotine.

Delivery of hydrocortisone from liposomal suspensions to the hairless mouse skin following topical application under non-occlusive and occlusive conditions.

The in-vivo cutaneous absorption of hydrocortisone was examined following topical application of hydrocortisone-containing liposomes. The formulation was applied onto the skin (1.0 cm2) of the hairless mouse (at a dose of 0.1 mg hydrocortisone) in the presence and absence of occlusion, and temporal profiles of the drug in the skin (stratum corneum and viable skin) were monitored. Under the non-occluded condition, the drug amount in the stratum corneum and viable skin reached its maximum within 1 h, and then decreased rapidly. Gelation of the liposomes by complete dehydration of the formulation under non-occlusion, which may prevent partition of the drug into the skin, appears to be a cause of the rapid decrease. Under the occluded condition, the drug amount in the skin was sustained although it then decreased dramatically compared with that under the non-occlusion (i.e. approximately 1/22 for stratum corneum and 1/8 for viable skin at 1 h, for example). A prevention of gelation of the liposomes by occlusion appears to be a potential mechanism of the maintenance of the drug concentration in the skin. The dramatic decrease in drug content in the skin may be attributed to the reduced partition of hydrocortisone, a hydrophobic drug, from the liposomes into the hydration-maintained stratum corneum under occlusion. In both application conditions, the concentration of hydrocortisone in the hydrophilic viable skin layer was markedly lower than that in the stratum corneum, indicating that partitioning between these tissues is a primary determinant of hydrocortisone reaching viable skin tissue. The estimated penetration depth of the drug into the stratum corneum was not affected significantly by the application conditions. These results demonstrate that excessive dehydration (non-occlusion) is not desirable for the prolonged delivery of hydrocortisone from liposomes into the skin. They also indicate that either hydration of the dosed skin (occlusion) is not preferable for the efficient delivery of hydrocortisone from the liposomes to the skin, especially to the viable skin. Therefore, both excessive dehydration of the liposomes and excessive hydration of the dosed skin (occlusion) should be avoided in the topical application of liposomal formulations for efficient delivery of hydrocortisone to the skin for a prolonged period of time.

Decreased Systemic Clearance of Diltiazem with Increased Hepatic Metabolism in Rats with Uranyl Nitrate-Induced Acute Renal Failure

The effect of uranyl nitrate (UN)-induced acute renal failure (ARF) on the pharmacokinetics of diltiazem (DTZ) was examined in rats through in vitro and in vivo studies. In vitro homogenate studies demonstrated that DTZ was metabolized to deacetyl diltiazem (DAD) predominantly in the liver. Metabolism in the small intestine, kidney, or blood pool was negligible compared with that in the liver. UN-induced ARF (UN-ARF) increased the in vitro hepatic clearance (CLvit) of DTZ 1.4-fold. In vivo pharmacokinetic studies following intravenous (iv) and portal venous (pv) administration revealed that UN-ARF increased the intrinsic clearance (CLi) of DTZ from 243.0 to 414.5 ml/min/kg but decreased its total plasma clearance (CLt) from 90.3 to 64.3 ml/min/kg. The increase in CLi was consistent with the increase in CLvit of the liver. The in vitro plasma free fraction of DTZ (fp) was decreased from 0.25 to 0.14 by UN-ARF, but the in vitro blood/plasma partition of DTZ (Rb) remained constant at unity. From the CLi and fp changes, the plasma intrinsic clearance for unbound DTZ (CLi′) was calculated to be increased 2.7-fold, from 1104.5 to 2960.7 ml/min/kg, by UN-ARF. The fp decrease was also reflected in the steady-state distribution volume (Vdss) of DTZ, which was decreased significantly from 3595.5 to 2528.3 ml/kg. The absolute bioavailability of pv DTZ (Fpv) was decreased by UN-ARF from 37.5 to 15.5% but was still much higher than the reported oral bioavailability (6%), indicating poor absorption of DTZ from the GI tract. From the calculation based on a well-stirred pharmacokinetic model, DTZ was found to increase the hepatic blood flow (HBF) of the control rats more than twofold at doses of 3 mg/kg (iv) or 10 mg/kg (pv), possibly due to the vasodilating effect of DTZ. However, the effect of DTZ on HBF was not present in the UN-ARF rats. It is not clear at present whether this could be attributed to vasoconstricting effects of UN-ARF or blockade of the vasodilating effect of DTZ.

Pharmacokinetics of diltiazem and deacetyldiltiazem in rats

Abstract Diltiazem (DTZ) was given intravenously (i.v.), orally (p.o.) and hepatoportally (p.v.) in solution form to rats in order to assess the pharmacokinetic behavior of DTZ and its major metabolite, deacetyldiltiazem (DAD). The plasma half-life at postdistributive phase ( t 1 2 ,β), total body (plasma) clearance (CL t ) and volume of distribution at steady-state (Vd ss ) of DTZ were 38.3 min, 90.3 ml/min per kg and 3595 ml/kg, respectively, for a 3 mg/kg i.v. dose. DAD was also given to rats through the i.v. route and its plasma pharmacokinetics was compared with that of DTZ. The t 1 2 ,β, CL t and Vd ss of DAD were 43.3 min, 82.4 ml/min per kg and 4042 ml/kg, respectively, for a 3 mg/kg i.v. dose. There was no significant difference in the pharmacokinetic parameters between DTZ and DAD. 20% of the i.v. dose was found to be metabolized to DAD in the body. Most of an oral dose of DTZ (30 mg/kg was extracted during its passage through the GI tract and only 15% of the dose was transported into the portal venous blood as an intact form. DTZ administered by the p.v. route (10 ml/kg) suffered hepatic extraction and 37% of the dose could reach the systemic circulation. As a consequence, bioavailability of only 6% could be obtained for the oral DTZ.

Simultaneous determination of loxoprofen and its diastereomeric alcohol metabolites in human plasma and urine by a simple HPLC-UV detection method

A simple, reliable HPLC-UV detection method was developed for the simultaneous determination of loxoprofen and its metabolites (i.e. trans- and cis-alcohol metabolites), in human plasma and urine samples. The method involves the addition of a ketoprofen (internal standard) solution in methanol, zinc sulfate solution and acetonitrile to plasma and urine samples, followed by centrifugation. An aliquot of the supernatant was evaporated to dryness, and the residue reconstituted in a mobile phase (acetonitrile:water=35:65 v/v, pH 3.0). An aliquot of the solution was then directly injected into the HPLC system. Separations were performed on octadecylsilica column (250x4.5 mm, 5 microm) with a guard column (3.2x1.5 cm, 7 microm) at ambient temperature. Loxoprofen and the metabolites in the eluent were monitored at 220 nm (a.u.f.s. 0.005). Coefficients of variations (CV%) and recoveries for loxoprofen and its metabolites were below 10 and over 96%, respectively, in the 200 approximately 15000 ng ml(-1) range for plasma and 500 approximately 50000 ng ml(-1) range for urine. Calibration curves for all the compounds in the plasma and urine were linear over the above-mentioned concentration ranges with a common correlation coefficient of 0.999. The detection limit of the present method was 100 ng for all the compounds. These results indicate that the present method is very simple and readily applicable to routine bioavailability studies of these compounds with an acceptable sensitivity.

Pharmacokinetics of talniflumate, a prodrug of niflumic acid, following oral administration to man

Plasma profile of niflumic acid following oral administration of talniflumate tablets (Somalgen) was compared to that of niflumic acid tablets in man. Plasma niflumic acid was assayed by HPLC method. Plasma niflumic acid profile from the talniflumate tablets was similar to that from the niflumic acid tablets resulting in no differences in AUC,Cmax,tmax and MRT. It demonstrates that talniflumate is a prodrug of niflumic acid, and undergoes extensive first-pass biotransformation to niflumic acid. However, plasma niflumic acid concentration at 30 min after talniflumate dosing was significantly (p<0.05) higher than that of niflumic acid dosing. The more potent analgesic activity of talniflumate than niflumic acid might be related to this higher plasma drug concentration at the earlier phase. Considering that talniflumate is less irritant to gastrointestinal mucosa than niflumic acid, talniflumate seems to be advantageous over niflumic acid in therms of activity and side effects.