Erratum - A Novel Model for Studying Voltage-Gated Ion Channel Gene Expression during Reversible Ischemic Stroke.

[This corrects the article DOI: 10.7150/ijms.27442.].

A Novel Model for Studying Voltage-Gated Ion Channel Gene Expression during Reversible Ischemic Stroke.

The dysfunction of voltage-gated ion channels contributes to the pathology of ischemic stroke. In this study, we developed rat models of transient ischemic attack (TIA) and reversible ischemic neurological deficit (RIND) that was induced via the injection of artificial embolic particles during full consciousness, that allow us to monitor the neurologic deficit and positron emission tomography (PET) scans in real-time. We then evaluated the infarction volume of brain tissue was confirmed by 2,3,5-triphenyl tetrazolium chloride (TTC) staining, and gene expressions were evaluated by quantitative real-time PCR (qPCR). We found that rats with TIA or RIND exhibited neurological deficits as determined by negative TTC and PET findings. However, the expression of voltage-gated sodium channels in the hippocampus was significantly up-regulated in the qPCR array study. Furthermore, an altered expression of sodium channel ß-subunits and potassium channels, were observed in RIND compared to TIA groups. In conclusion, to our knowledge, this is the first report of the successful evaluation of voltage-gated ion channel gene expression in TIA and RIND animal models. This model will aid future studies in investigating pathophysiological mechanisms, and in developing new therapeutic compounds for the treatment of TIA and RIND.

Development of pH-Sensitive Cationic PEGylated Solid Lipid Nanoparticles for Selective Cancer-Targeted Therapy.

Solid lipid nanoparticles (SLNs) are suitable candidates for the delivery of various anti-cancer drugs. However, currently insufficient tumor-permeability and non-specific uptake by the reticuloendothelial system limits the application of SLNs. Here, we developed novel pH-sensitive cationic polyoxyethylene (PEGylated) SLNs (PEG-SLNs+) that could accumulate long-term at various tumor sites to enhance the therapeutic efficiency of camptothecin (CPT). These CPT-loaded PEG-SLNs+ (CPT-PEG-SLNs+) were spherical nanoparticles, with small size (∼52.3±1.7 nm), positive charge (∼34.3±3.5 mV) and high entrapment efficiency (∼99.4±1.7%). Drug release profile indicated the overall released amount of CPT from CPT-PEG-SLNs+ at pH 5.5 was 20.2% more than at pH 7.4, suggesting CPT-PEG-SLNs+ were a pH-sensitive SLNs. This PEG-SLNs+ could be efficiently uptaken into cells to inhibit the proliferation of CL1-5 cells (IC50 = 0.37 ±0.21 ug/ml) or HCC36 cells (IC50 = 0.16±0.43 ug/ml). In living animal, our PEG-SLNs+ could accumulate long-term (for more than 120 hours) in various types of tumor, including human lung carcinoma (NCI-H358, CRL5802, CL1-5), human colon carcinoma (HCT-116) and human hepatocellular carcinoma (HCC36), and CPT-PEG-SLNs+ could efficiently enhance the therapeutic efficiency of CPT to suppress the growth of the HCC36 or CL1-5 tumors. Therefore, Successful development of these pH-sensitive PEGylated cationic SLNs may provide a selective and efficient drug delivery system for cancer therapy.

The Influence of Acute Hyperglycemia in an Animal Model of Lacunar Stroke That Is Induced by Artificial Particle Embolization.

Animal and clinical studies have revealed that hyperglycemia during ischemic stroke increases the stroke's severity and the infarct size in clinical and animal studies. However, no conclusive evidence demonstrates that acute hyperglycemia worsens post-stroke outcomes and increases infarct size in lacunar stroke. In this study, we developed a rat model of lacunar stroke that was induced via the injection of artificial embolic particles during full consciousness. We then used this model to compare the acute influence of hyperglycemia in lacunar stroke and diffuse infarction, by evaluating neurologic behavior and the rate, size, and location of the infarction. The time course of the neurologic deficits was clearly recorded from immediately after induction to 24 h post-stroke in both types of stroke. We found that acute hyperglycemia aggravated the neurologic deficit in diffuse infarction at 24 h after stroke, and also aggravated the cerebral infarct. Furthermore, the infarct volumes of the basal ganglion, thalamus, hippocampus, and cerebellum but not the cortex were positively correlated with serum glucose levels. In contrast, acute hyperglycemia reduced the infarct volume and neurologic symptoms in lacunar stroke within 4 min after stroke induction, and this effect persisted for up to 24 h post-stroke. In conclusion, acute hyperglycemia aggravated the neurologic outcomes in diffuse infarction, although it significantly reduced the size of the cerebral infarct and improved the neurologic deficits in lacunar stroke.

Amsacrine analog-loaded solid lipid nanoparticle to resolve insolubility for injection delivery: characterization and pharmacokinetics.

Amsacrine analog is a novel chemotherapeutic agent that provides potentially broad antitumor activity when compared to traditional amsacrine. However, the major limitation of amsacrine analog is that it is highly lipophilic, making it nonconductive to intravenous administration. The aim of this study was to utilize solid lipid nanoparticles (SLN) to resolve the delivery problem and to investigate the biodistribution of amsacrine analog-loaded SLN. Physicochemical characterizations of SLN, including particle size, zeta potential, entrapment efficiency, and stability, were evaluated. In vitro release behavior was also measured by the dialysis method. In vivo pharmacokinetics and biodistribution behavior of amsacrine analog were investigated and incorporated with a non invasion in vivo imaging system to confirm the localization of SLN. The results showed that amsacrine analog-loaded SLN was 36.7 nm in particle size, 0.37 in polydispersity index, and 34.5±0.047 mV in zeta potential. More than 99% of amsacrine analog was successfully entrapped in the SLN. There were no significant differences in the physicochemical properties after storage at room temperature (25°C) for 1 month. Amsacrine analog-loaded SLN maintained good stability. An in vitro release study showed that amsacrine analog-loaded SLN sustained a release pattern and followed the zero equation. An in vivo pharmacokinetics study showed that amsacrine analog was rapidly distributed from the central compartment to the tissue compartments after intravenous delivery of amsacrine analog-loaded SLN. The biodistribution behavior demonstrated that amsacrine analog mainly accumulated in the lungs. Noninvasion in vivo imaging system images also confirmed that the drug distribution was predominantly localized in the lungs when IR-780-loaded SLN was used.

Long-acting Inhaled Bronchodilator and Risk of Vascular Events in Patients With Chronic Obstructive Pulmonary Disease in Taiwan Population.

A combination of long-acting anticholinergic agents (LAACs) and long-acting ß2-adrenergic receptor agonist (LABA) is effective in improving lung function in chronic obstructive pulmonary disease (COPD) compared with monotherapy. However, evidence on whether this combination increases the incidence of stroke or other cardiac events remains sparse. The objective of the present study was to investigate the incidence of stroke and other cardiovascular diseases in COPD patients treated with LAAC, LABA, or a combination of the 2.We conducted this population-based study using the Taiwan National Health Insurance Research Database (1997-2008), identifying COPD patients and their prescribed medication from the International Classification of Disease, Ninth Revision codes 490-492 or 496. A multivariate Cox proportional-hazards model was used to compare the risk of stroke and other cardiovascular diseases over the 11-year period after treatment with LAAC or LABA only or in combination.Of the 596 COPD patients (mean age 70 y), 196 were treated with LAAC, 318 with LABA, and 82 were treated with a combination. The overall incidence of stroke (8.53%) significantly increased in the combination group compared with LAAC (2.04%) or LABA (1.26%) only. In the Cox regression analysis, the adjusted hazard ratio over the 11-year survey period for stroke in patients treated with the combination compared with LABA only was 1.04 (95% confidence interval, 1.06-2.99) and for LAAC, it was 0.31 (95% confidence interval, 0.02-2.32).This cohort study using a large health insurance database showed that treating patients with COPD, with a combination of LAAC and LABA, may be associated with an increased hazard of stroke compared with treatment with either agent alone. We should be particularly cautious about comedication of LAAC and LABA in patients with COPD.

8-Oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine concentrations in various human body fluids: implications for their measurement and interpretation.

8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is the most investigated product of oxidatively damaged DNA lesion that has been associated with the development of aging, cancer and some degenerative diseases. Here, we present the first liquid chromatography-tandem mass spectrometry method that enables the simultaneous measurement of its repair products in plasma and saliva, namely 8-oxo-7,8-dihydroguanine (8-oxoGua) and 8-oxodGuo. Using this method, we investigated the underlying transport mechanism of the repair products of oxidatively damaged DNA between cellular compartments and biological matrices. Plasma, saliva and urine samples were collected concurrently from 57 healthy subjects. Various deproteinization methods were evaluated, and the precipitants acetonitrile and sodium hydroxide-methanol were, respectively, selected for plasma and saliva samples due to their effect on recovery efficiencies and chromatography. The mean baseline concentrations of 8-oxoGua and 8-oxodGuo in plasma were demonstrated to be 0.21 and 0.016 ng/mL, respectively, while in saliva they were 0.85 and 0.010 ng/mL, respectively. A relatively high concentration of 8-oxoGua was found in saliva with a concentration factor (CF, concentration ratio of saliva to plasma) of 4 as compared to that of 8-oxodGuo (CF: 0.6), implying that 8-oxoGua in plasma may be actively transported to saliva, whereas 8-oxodGuo was most dependent on a passive diffusion. Good correlations between urine and plasma concentrations were observed for 8-oxoGua and 8-oxodGuo, suggesting that blood was a suitable matrix in addition to urine. Significant correlation between 8-oxoGua and 8-oxodGuo in urine was only observed when the concentrations were not corrected for urinary creatinine, raising the issue of applicability of urinary creatinine to adjust 8-oxoGua concentrations.

Anti-oxidant activity and attenuation of bladder hyperactivity by the flavonoid compound kaempferol.

OBJECTIVES: To evaluate the anti-oxidant activity of the flavonoid compound, kaempferol, and to examine its role in the suppression of oxidative stress and attenuation of bladder hyperactivity in a rat model of bladder injury. METHODS: The anti-oxidative activity of kaempferol was examined in lipopolysaccharide-treated RAW264.7 macrophages by using flow cytometry. For in vivo studies, rats were pretreated with kaempferol or vehicle for 24 h. The rat urothelium was injured by the administration of protamine sulfate for 1.5 h and irritated by the subsequent infusion of potassium chloride for 4 h. Oxidative stress in the bladder tissue was assessed using chemiluminescence assay, and the bladder pressure was determination by cystomertrogram. RESULTS: Kaempferol significantly suppressed lipopolysaccharide-induced reactive oxygen species production in RAW264.7 rat macrophages. Exposure of the rat bladder to sequential infusion of protamine sulfate and potassium chloride induced bladder hyperactivity. Pretreatment with kaempferol, prevented the formation of reactive oxygen species and prolonged the intercontraction interval. CONCLUSION: Kaempferol suppresses oxidative stress and attenuates bladder hyperactivity caused by potassium chloride after protamine sulfate-induced bladder injury.

Isotretinoin oil-based capsule formulation optimization.

The purpose of this study was to develop and optimize an isotretinoin oil-based capsule with specific dissolution pattern. A three-factor-constrained mixture design was used to prepare the systemic model formulations. The independent factors were the components of oil-based capsule including beeswax (X1), hydrogenated coconut oil (X2), and soybean oil (X3). The drug release percentages at 10, 30, 60, and 90 min were selected as responses. The effect of formulation factors including that on responses was inspected by using response surface methodology (RSM). Multiple-response optimization was performed to search for the appropriate formulation with specific release pattern. It was found that the interaction effect of these formulation factors (X1X2, X1X3, and X2X3) showed more potential influence than that of the main factors (X1, X2, and X3). An optimal predicted formulation with Y(10 min), Y(30 min), Y(60 min), and Y(90 min) release values of 12.3%, 36.7%, 73.6%, and 92.7% at X1, X2, and X3 of 5.75, 15.37, and 78.88, respectively, was developed. The new formulation was prepared and performed by the dissolution test. The similarity factor f2 was 54.8, indicating that the dissolution pattern of the new optimized formulation showed equivalence to the predicted profile.

Effect of microemulsions on transdermal delivery of citalopram: optimization studies using mixture design and response surface methodology.

The aim of this study was to evaluate the potential of microemulsions as a drug vehicle for transdermal delivery of citalopram. A computerized statistical technique of response surface methodology with mixture design was used to investigate and optimize the influence of the formulation compositions including a mixture of Brij 30/Brij 35 surfactants (at a ratio of 4:1, 20%-30%), isopropyl alcohol (20%-30%), and distilled water (40%-50%) on the properties of the drug-loaded microemulsions, including permeation rate (flux) and lag time. When microemulsions were used as a vehicle, the drug permeation rate increased significantly and the lag time shortened significantly when compared with the aqueous control of 40% isopropyl alcohol solution containing 3% citalopram, demonstrating that microemulsions are a promising vehicle for transdermal application. With regard to the pharmacokinetic parameters of citalopram, the flux required for the transdermal delivery system was about 1280 µg per hour. The microemulsions loaded with citalopram 3% and 10% showed respective flux rates of 179.6 µg/cm(2) and 513.8 µg/cm(2) per hour, indicating that the study formulation could provide effective therapeutic concentrations over a practical application area. The animal study showed that the optimized formulation (F15) containing 3% citalopram with an application area of 3.46 cm(2) is able to reach a minimum effective therapeutic concentration with no erythematous reaction.

The transport effect of submicron emulsions on 5-flurouracil topical application.

Water-in-oil submicron emulsions were used as carrier for the topical delivery of 5-fluorouracil (5FU). The effect of components such as level and hydrophilic-lipophilic balance (HLB) value of surfactant, type of cosurfactant, and drug concentration on the delivery capability of drug in the receptor fluid and in the various skin layers (stratum corneum, epidermis and dermis) were evaluated. The result showed the submicron emulsion could increase the transdermal and deposition of 5FU compared with the aqueous control. Submicron emulsion with surfactant at HLB of 6.0 had higher deposition amount of drug in epidermis layer. The deposition amount of drug in the skin layers increased with increased amounts of surfactant and drug loading of submicron emulsion. However, the 0.2% 5FU-load submicron emulsion showed a comparable deposition effect in various skin layers with the commercial product (5%, Efudix®), which indicated that the submicron emulsions could be a promising drug vehicle for topical application.

Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4) to enhance solubility for injection delivery.

BACKGROUND: The synthetic potential chemotherapeutic agent 3-Chloro-4-[(4-methoxyphenyl) amino]furo[2,3-b]quinoline (PK-L4) is an analog of amsacrine. The half-life of PK-L4 is longer than that of amsacrine; however, PK-L4 is difficult to dissolve in aqueous media, which is problematic for administration by intravenous injection. AIMS: To utilize solid lipid nanoparticles (SLNs) modified with polyethylene glycol (PEG) to improve the delivery of PK-L4 and investigate its biodistribution behavior after intravenous administration. RESULTS: The particle size of the PK-L4-loaded SLNs was 47.3 nm and the size of the PEGylated form was smaller, at 28 nm. The entrapment efficiency (EE%) of PK-L4 in SLNs with and without PEG showed a high capacity of approximately 100% encapsulation. Results also showed that the amount of PK-L4 released over a prolonged period from SLNs both with and without PEG was comparable to the non-formulated group, with 16.48% and 30.04%, respectively, of the drug being released, which fit a zero-order equation. The half-maximal inhibitory concentration values of PK-L4-loaded SLNs with and those without PEG were significantly reduced by 45%-64% in the human lung carcinoma cell line (A549), 99% in the human breast adenocarcinoma cell line with estrogen receptor (MCF7), and 95% in the human breast adenocarcinoma cell line (MDA-MB-231). The amount of PK-L4 released by SLNs with PEG was significantly higher than that from the PK-L4 solution (P < 0.05). After intravenous bolus of the PK-L4-loaded SLNs with PEG, there was a marked significant difference in half-life alpha (0.136 ± 0.046 hours) when compared with the PK-L4 solution (0.078 ± 0.023 hours); also the area under the curve from zero to infinity did not change in plasma when compared to the PK-L4 solution. This demonstrated that PK-L4-loaded SLNs were rapidly distributed from central areas to tissues and exhibited higher accumulation in specific organs. The highest deposition of PK-L4-loaded SLNs with PEG was found in the lung and spine. CONCLUSION: Sufficient amounts of PK-L4 were entrapped in the SLNs, and the pharmacokinetic behavior of PK-L4-loaded SLNs was established. This formulation successfully resolved the delivery problem, and the drug was localized in particular organs.

The effect of submicron emulsion systems on transdermal delivery of kaempferol.

In this study, submicron emulsions have been employed as a carrier for the topical application of kaempferol. The effect of components of submicron emulsions on the physicochemical properties and permeation capability of drug were evaluated. In case of drug-loaded submicron emulsions, the cumulative amount over 12 h (Q(12 h)), lag time and deposition in skin amount ranged from 13.0±3.4 to 236.1±21.2 µg/cm(2), 1.7 to 5.3 h, and 1.10 to 7.76 µg/cm(2), respectively, which indicated that the permeation parameters of kaempferol were markedly influenced by the component ratio. Kaempferol dispensed in isopropyl myristate was used as the control. The Q(12 h), lag time and deposition amount in skin were 4.2±1.8 µg/cm(2), 6.0 h and 2.25±0.60 µg/cm(2), respectively. The data showed that used appropriate submicron emulsions as vehicle could significantly increase the Q(12 h) and deposition amount in skin and shorten the lag time, demonstrating that submicron emulsions have a potent enhancement effect for kaempferol transdermal delivery.

Baicalein loaded in tocol nanostructured lipid carriers (tocol NLCs) for enhanced stability and brain targeting.

The objective of the present work was to investigate the specific brain targeting of baicalein by intravenous injection after incorporation into nanostructured lipid carriers (NLCs). The NLC system, composed of tripalmitin, Gelucires, vitamin E, phospholipids, and poloxamer 188 (referred to as tocol NLCs), was characterized in terms of its physicochemical properties, differential scanning calorimetry (DSC), stability, in vivo pharmacokinetics, and brain distribution. The lipid nanoparticles were spherical with an average size of ∼100 nm. The zeta potential of the nanoparticles was about -50 mV. DSC studies suggested that the majority of the inner cores of tocol NLCs had a slightly disordered crystal arrangement. The nanoparticulate dispersions demonstrated good physical stability during storage for 6 days. The incorporation of vitamin E in the formulations greatly reinforced baicalein's stability. The aqueous control and tocol NLCs were intravenously administered to rats. The plasma level of baicalein in NLCs was much higher and the half-life much longer than those in the free control. In the experiment on the brain distribution, NLCs respectively revealed 7.5- and 4.7-fold higher baicalein accumulations compared to the aqueous solution in the cerebral cortex and brain stem. Greater baicalein accumulations with NLCs were also detected in the hippocampus, striatum, thalamus, and olfactory tract. A 2-3-fold increase in baicalein amounts were achieved in these regions. Tocol NLCs improved baicalein's stability and the ability of baicalein to penetrate the brain; thus, this is a promising drug-targeting system for the treatment of central nervous system disorders.

Formulation optimization of transdermal meloxicam potassium-loaded mesomorphic phases containing ethanol, oleic acid and mixture surfactant using the statistical experimental design methodology.

Response surface methodology (RSM) was used to develop and optimize the mesomorphic phase formulation for a meloxicam transdermal dosage form. A mixture design was applied to prepare formulations which consisted of three independent variables including oleic acid (X(1)), distilled water (X(2)) and ethanol (X(3)). The flux and lag time (LT) were selected as dependent variables. The result showed that using mesomorphic phases as vehicles can significantly increase flux and shorten LT of drug. The analysis of variance showed that the permeation parameters of meloxicam from formulations were significantly influenced by the independent variables and their interactions. The X(3) (ethanol) had the greatest potential influence on the flux and LT, followed by X(1) and X(2). A new formulation was prepared according to the independent levels provided by RSM. The observed responses were in close agreement with the predicted values, demonstrating that RSM could be successfully used to optimize mesomorphic phase formulations.

Characterization of the pattern of ischemic stroke induced by artificial particle embolization in the rat brain.

Embolism is responsible for half of cerebral infarctions, yet few animal models were developed due to the unpredictability of the embolus-induced infarcts. We manufactured artificial embolic particles by blending chitin and poly(D,L-Lactide-co-glycolide) (chitin/PLGA) for their good biocompatibility and rapid hydration expansion property. We subdivided the chitin/PLGA microparticles into 10 size groups (from 38-45 µm to 255-350 µm) and injected them through the external carotid artery toward the bifurcation of the common carotid artery in the rat. Reduced blood flow of the ipsilateral hemisphere was evident immediately after the injection of particles. The spherical appearance of the particle was critical in occluding the cerebral vessels. Particle(212-250 µm) produced the greatest diffuse infarction in the ipsilateral hemisphere, including the cortex, hippocampus, basal ganglion, thalamus, midbrain and cerebellum. Particle(75-90 µm) induced single or sparse isolated infarcts mainly located in the subcortical region, resembling lacunar stroke observed in humans. Particle(38-45 µm) frequently crossed to the contralateral hemisphere and induced diffuse infarctions in both hemispheres. The cortex infarct volumes were positively correlated to neurologic score and seizure incidence. In conclusion, we have established embolic stroke animal models, including a novel model that mainly expresses lacunar infarction, by intravenous injection of chitin/PLGA microparticles.

Formulation optimization of estradiol microemulsion using response surface methodology.

The aim of the current study was to find an optimal estradiol-loaded microemulsion with higher permeation rate and shortened lag time (LT) for transdermal application by using a response surface methodology (RSM) and constrained mixture design. Isopropyl myristate (X1 ), distilled water (X2 ), and ethanol (X3 ) were selected as independent variables, whereas the viscosity of microemulsion and permeation parameters including the cumulative amount at 24 h (Q24h ) and LT of estradiol-loaded microemulsion through skin were set as dependent variables. The result showed that the three independent variables had a remarkable effect (p < 0.05) on the dependent variables. Moreover, the predicted and observed values of these three dependent variables of the optimal microemulsion formulations, which were produced by the RSM optimization technique, were close, demonstrating that RSM was a useful technique for optimizing pharmaceutical formulations. However, the experimental estradiol-loaded microemulsion with higher permeation rate was expected to provide effective therapeutic concentration in a workable administration area.

Elastic liposomes as carriers for oral delivery and the brain distribution of (+)-catechin.

The aim of this work was to investigate whether the oral bioavailability and brain regional distribution of (+)-catechin could be improved by utilizing elastic liposomes. Liposomes containing soy phosphatidylcholine, cholesterol, and Tween 80 in the presence of 15% ethanol were prepared by a thin-film method and subsequent sonication and extrusion. The size, zeta potential, and stability of the liposomes in simulated gastrointestinal (GI) media were characterized. The mean size of liposomes was 35-70 nm, which decreased with an increase in the Tween 80 concentration. The zeta potential of the system was about-15 mV. More than 80% of the (+)-catechin was entrapped in the aqueous core of liposomes produced with 1% Tween 80. Liposomes entrapping (+)-catechin remained stable in the presence of GI fluids, especially in simulated intestinal fluid. The liposomes showed suppressed and sustained release of (+)-catechin compared with that from an aqueous solution. The aqueous control and liposomes were orally administered to rats. The blood level of liposomal (+)-catechin was enhanced at a later stage after administration compared with the free control. In the experiment on the brain distribution, liposomes with elastic properties showed 2.9- and 2.7-fold higher (+)-catechin accumulations compared with the aqueous solution in the cerebral cortex and hippocampus, respectively. Greater compound accumulations with liposomes were also detected in the striatum and thalamus. The experimental results suggest that elastic liposomes may offer a promising strategy for improving (+)-catechin delivery via oral ingestion.

The effect of component of microemulsions on transdermal delivery of buspirone hydrochloride.

The aim of this study was to evaluate the influence of components such as type, level, and hydrophilic-lipophilic balance (HLB) value of surfactant, type and amount of cosurfactant, and drug concentration on the permeability of buspirone hydrochloride microemulsions through rat skin. The cumulative amount at 24 h ranged from 502.2 ± 57.8 to 1754.3 ± 616.6 µg/cm(2), flux ranged from 23.03 ± 1.84 to 83.36 ± 25.08 µg/(cm(2)/h), and lag time ranged from 3.0 to 4.7 h, indicating that the permeation parameters of buspirone from microemulsions were markedly influenced by the composition of microemulsions. In comparison with the effect of composition of microemulsions on the buspirone permeation capacity, it was found that microemulsions containing surfactant with HLB value of 11.16 possessed higher flux. The viscosity of microemulsions increased, flux decreased, and lag time was prolonged when amount of surfactant in microemulsions increased. The various cosurfactants can also influence the microemulsion formation and drug permeability. The microemulsion with ethanol as cosurfactant had higher permeation rate. However, the buspirone microemulsion with higher flux can provide the therapeutic minimum effective concentration, at workable administrated area about 3.3-5.8 cm(2), demonstrating microemulsions could be a promising drug carrier for transdermal delivery systems.

Oral apomorphine delivery from solid lipid nanoparticles with different monostearate emulsifiers: pharmacokinetic and behavioral evaluations.

Apomorphine, a dopamine receptor agonist for treating Parkinson's disease, has very poor oral bioavailability (<2%) due to the first-pass effect. The aim of this work was to investigate whether the oral bioavailability and brain regional distribution of apomorphine could be improved by utilizing solid lipid nanoparticles (SLNs). Glyceryl monostearate (GMS) and polyethylene glycol monostearate (PMS) were individually incorporated into SLNs as emulsifiers. It was found that variations in the emulsifiers had profound effects on the physicochemical characteristics. Mean diameters of the GMS and PMS systems were 155 and 63 nm, respectively. More than 90% of the apomorphine was entrapped in the SLNs. The interfacial film was the likely location for most of apomorphine molecules. The PMS system, when incubated in simulated intestinal medium, was found to be more stable in terms of particle size and encapsulation efficiency than the GMS system. Using the GMS and PMS systems to orally administer apomorphine (26 mg/kg) equally enhanced the bioavailability in rats. SLNs showed 12- to 13-fold higher bioavailability than the reference solution. The drug distribution in the striatum, the predominant site of therapeutic action, also increased when using the SLNs. The anti-Parkinsonian activity of apomorphine was evaluated in rats with 6-hydroxydopamine-induced lesions, a model of Parkinson's disease. The contralateral rotation behavior was examined after oral apomorphine delivery. The total number of rotations increased from 20 to 94 and from 20 to 115 when the drug was administered from SLNs containing GMS and PMS, respectively. The experimental results suggest that SLNs may offer a promising strategy for apomorphine delivery via oral ingestion.