Intranasal drug delivery of olanzapine-loaded chitosan nanoparticles.

The aim of this study was to investigate olanzapine (OZ) systemic absolute bioavailability after intranasal (i.n.) administration in vivo to conscious rabbits. Furthermore, the study investigated the potential use of chitosan nanoparticles as a delivery system to enhance the systemic bioavailability of olanzapine following intranasal administration. Olanzapine-loaded chitosan nanoparticles were prepared through ionotropic gelation of chitosan with tripolyphosphate anions and studied in terms of their size, drug loading, and in vitro release. The OZ nanoparticles were administered i.n. to rabbits, and OZ plasma concentration at predetermined time points was compared to i.n. administration of OZ in solution. The concentrations of OZ in plasma were analyzed by ultra performance liquid chromatography mass spectroscopy (UPLC/MS). OZ-loaded chitosan nanoparticles significantly (p < 0.05) enhanced systemic absorption with 51 ± 11.2% absolute bioavailability as compared to 28 ± 6.7% after i.n. administration of OZ solution. The results of the present study suggest that intranasal administration of OZ-loaded chitosan nanoparticles formulation could be an attractive modality for delivery of OZ systemically.

Bioavailability of Δ9-tetrahydrocannabinol following intranasal administration of a mucoadhesive gel spray delivery system in conscious rabbits.

BACKGROUND: The purpose of this study was to investigate the potential of the intranasal route for systemic delivery of solubilized Δ9-tetrahydrocannabinol (THC). A further aim was to investigate the effect of nasally administered chitosan-based nasal bioadhesive gel on THC bioavailability as a formulation strategy to decrease normal mucociliary drug clearance. METHOD: The THC formulations were administered intranasally and compared to intravenous administration utilizing conscious rabbits. RESULTS: After nasal administration, the THC nasal solution afforded a C(max) value of 20 ± 3 ng/mL at 20 minutes. Interestingly, the THC loaded in chitosan gel formulation followed almost the same profile at early time points and subsequently afforded a higher C(max) value of 31 ± 4 ng/mL (T(max) = 45 minutes). The absolute bioavailability of THC after nasal delivery was studied to compare plasma THC concentrations after nasal administration with those after intravenous injection. Absolute bioavailability values were 13.3 ± 7.8% and 15.4 ± 6.5% for the THC nasal solution and gel formulations, respectively. CONCLUSION: The results of the present study suggest that intranasal administration of THC in solution or in a chitosan-based nasal gel formulation could be an attractive modality for delivery of THC systemically.

Intranasal drug delivery of didanosine-loaded chitosan nanoparticles for brain targeting; an attractive route against infections caused by AIDS viruses.

The primary aim of this study was to investigate intranasal (i.n.) administration as a potential route to enhance systemic and brain delivery of didanosine (ddI). A further aim was to investigate the potential use of chitosan nanoparticles as a delivery system to enhance the systemic and brain targeting efficiency of ddI following i.n. administration. Didanosine-loaded chitosan nanoparticles, were prepared through ionotropic gelation of chitosan with tripolyphosphonate anions, and characterized in terms of their size, drug loading, and in vitro release. The nanoparticles were administered i.n. to rats, compared to i.n. and intravenous (i.v.) administration of ddI in solution. The concentrations of ddI in blood, CSF, and brain tissues were analyzed by ultra performance liquid chromatography mass spectroscopy (UPLC/MS). The brain/plasma, olfactory bulb/plasma and CSF/plasma concentration ratios were significantly higher (P < 0.05) after i.n. administration of ddI nanoparticles or solution than those after i.v. administration of didanosine aqueous solution. The ratio of ddI concentration values of the nanoparticles to the solution at 180 min post-i.n. dosing was 2.1 and 1.9 in CSF and brain, respectively. Thus, both the i.n. route of administration and formulation of ddI in chitosan nanoparticles increased delivery of ddI to CSF and brain.

Intratumoral delivery of Paclitaxel in solid tumor from biodegradable hyaluronan nanoparticle formulations.

In the current study, novel paclitaxel-loaded cross-linked hyaluronan nanoparticles were engineered for the local delivery of paclitaxel as a prototype drug for cancer therapy. The nanoparticles were prepared using a desolvation method with polymer cross-linking. In vitro cytotoxicity studies demonstrated that less than 75% of the MDA-MB-231 and ZR-75-1 breast cancer cells were viable after 2-day exposure to paclitaxel-loaded hyaluronan nanoparticles or free paclitaxel, regardless of the dose. These results suggest that hyaluronan nanoparticles maintain the pharmacological activity of paclitaxel and efficiently deliver it to the cells. Furthermore, in vivo administration of the drug-loaded nanoparticles via direct intratumoral injection to 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor in female rats was studied. The paclitaxel-loaded nanoparticles treated group showed effective inhibition of tumor growth in all treated rats. Interestingly, there was one case of complete remission of tumor nodule and two cases of persistent reduction of tumor size that was observed on subsequent days. In the case of free paclitaxel-treated group, the mean tumor volume increased almost linearly (R(2) = 0.93) with time to a size that was 4.9-fold larger than the baseline volume at 57 days post-drug administration. Intratumoral administration of paclitaxel-loaded hyaluronan nanoparticles could be a promising treatment modality for solid mammary tumors.

Nicotine exposure can be detected in cerebrospinal fluid of active and passive smokers.

A simple, rapid and sensitive liquid chromatography/mass spectrometry (LC/MS) method has been utilized for the quantitative determination of nicotine and its major metabolite cotinine (COT) in human cerebrospinal fluid (CSF) of active and passive smokers. CSF samples from 18 smokers, 15 non-smokers, 15 children, 15 infants, and 9 neonatal were analyzed for nicotine (NIC) and cotinine content. Cotinine levels in the CSF of smokers ranged from 27.3 to 457.1 ng/ml, whereas nicotine levels were considerably lower (6.0-215.1 ng/ml). Cotinine could be detected in 4 of the 15 CSF samples from non-smokers (3.5-30.4 ng/ml), and a few other passive smokers, including neonates from smoking mothers (15.6-81.1 ng/ml). The concentrations of cotinine in CSF samples suggests that nicotine easily passes into the CSF, which makes it an excellent CSF marker for tobacco-smoke exposure.

An HPLC method for the simultaneous determination of neurotoxic dipyridyl isomers in human plasma.

Several studies on dipyridyl isomers have suggested that they are neurotoxic and that chronic exposure to these compounds could be a potential human health hazard. A reversed phase HPLC method was developed for the simultaneous quantitation of 2,2'-dipyridyl and its four positional isomers, 2,3'-, 2,4'-, 3,4'- and 4,4'-dipyridyl in human plasma. Plasma samples were basified, extracted with 1-chlorobutane, evaporated, the residue reconstituted in mobile phase, and an aliquot part was analyzed by HPLC. Chromatographic separations were performed on a C(18) reversed phase Sunfire column eluted with a mobile phase composed of potassium phosphate (pH 3.5; 25 mM)-acetonitrile (80:20, v/v). Isomers were separated with good resolution, and quantification was determined utilizing an internal standard of quinoxaline. The method has been validated over a range from 30 to 2000 ng/ml with correlation coefficients higher than 0.995. Extraction recoveries for the dipyridyl isomers averaged from 65 to 92%. Limit of detection and limit of quantitation for the dipyridyl isomers ranged from 15 to 70 ng/ml and 30 to 90 ng/ml, respectively. The inter- and intra-day variation did not exceed 7% with an accuracy range of 96-102%. The described analytical method was successfully utilized for the determination of dipyridyl isomers in human plasma and suggested the need for more routine monitoring of tobacco smokers and other individuals who are involuntarily exposed to environmental source of dipyridyl isomers.

Scopolamine sublingual spray: an alternative route of delivery for the treatment of motion sickness.

The purpose of this study was to develop a sublingual drug delivery spray formulation of scopolamine hydrobromide (L-(-)-hyoscine hydrobromide) and to determine the absolute bioavailability of scopolamine hydrobromide following sublingual delivery and to investigate the effect of a bioadhesive on the pharmacokinetic parameters of this drug in a rabbit model. Rabbits received a single scopolamine free base equivalent sublingual dose of 100 microg/kg and this was compared to intravenous administration of the drug. Blood samples were collected at different time points, and plasma scopolamine concentrations were determined using a new sensitive and specific LC/MS analytical method which utilized electrospray ionization detection. The bioavailability of sublingual scopolamine was determined by comparing plasma concentrations after sublingual spray delivery with equivalent intravenous doses. Following delivery of the sublingual spray dose, the average Cmax was 1024.4+/-177 ng/mL, and the AUC value was found to be 61067.6+/-9605 ng.min/mL. Relative to the intravenous dose (100% bioavailability), the bioavailability was 79.8% after sublingual spray administration. The addition of 2% chitosan, a bio-adhesive material and an absorption enhancer, showed a significant improvement in scopolamine sublingual absorption (p<0.05) was observed. Considering the limitations of delivering scopolamine orally or transdermally to patients who experience motion sickness, the sublingual route of administration using a spray delivery dosage form, is a potential alternative modality for the prevention of nausea and vomiting associated with motion sickness.

Effect of pH on sublingual absorption of oxycodone hydrochloride.

The purpose of this study was to develop a sublingual spray drug delivery formulation of oxycodone and evaluate the effect of formulation pH on sublingual absorption of oxycodone for acute pain management using rabbit as the animal model. Using a new, sensitive, and specific liquid chromatography/mass spectrometry (LC/MS) with electrospray ionization detector assay, the absorption bioavailability of sublingual oxycodone was determined in rabbits by comparing plasma concentration after sublingual spray delivery with equivalent intravenous dose. The effect of formulation pH on sublingual absorption of oxycodone was also tested on rabbits that had received oxycodone sublingually at a dose of 0.1 mg/0.1 mL (pH 4.0 and 9.0). Blood samples were collected at different time points, and plasma oxycodone concentrations were determined by LC/MS. Following administration of a 0.1 mg dose, the average C(max) values were found to be 64.9 +/- 12.1 and 95.2 +/- 10.1 ng/mL, for pH 4.0 and 9.0, respectively. The area under the curve (AUC) values were found to be 5807.0, and 8965.3 ng.min/mL for formulation pH 4.0 and 9.0, respectively. The mean sublingual bioavailability of oxycodone was 45.4% +/- 20.1% and 70.1% +/- 17.9%, for pH 4.0 and 9.0, respectively. The formulation pH had no significant influence on oxycodone bioavailability (P < .05). A sublingual spray dosage form of oxycodone hydrochloride would be a good alternative for fast onset pain management, especially in children.

Effect of pH on sublingual absorption of oxycodone hydrochloride.

The purpose of this study was to develop a sublingual spray drug delivery formulation of oxycodone and evaluate the effect of formulation pH on sublingual absorption of oxycodone for acute pain management using rabbit as the animal model. Using a new, sensitive, and specific liquid chromatography/mass spectrometry (LC/MS) with electrospray ionization detector assay, the absorption bioavailability of sublingual oxycodone was determined in rabbits by comparing plasma concentration after sublingual spray delivery with equivalent intravenous dose. The effect of formulation pH on sublingual absorption of oxycodone was also tested on rabbits that had received oxycodone sublingually at a dose of 0.1 mg/0.1 mL (pH 4.0 and 9.0). Blood samples were collected at different time points, and plasma oxycodone concentrations were determined by LC/MS. Following administration of a 0.1 mg dose, the average Cmax values were found to be 64.9±12.1 and 95.2±10.1 ng/mL, for pH 4.0 and 9.0, respectively. The area under the curve (AUC) values were found to be 5807.0, and 8965.3 ng.min/mL for formulation pH 4.0 and 9.0, respectively. The mean sublingual bioavailability of oxycodone was 45.4%±20.1% and 70.1%±17.9%, for pH 4.0 and 9.0, respectively. the formulation pH had no significant influence on oxycodone bioavailability (P<.05). A sublingual spray dosage form of oxycodone hydrochloride would be a good alternative for fast onset pain management, especially in children.