Influence Of Absorption Enhancers Research Articles

Effect of Different Absorption Enhancers on the Nasal Absorption of Nalmefene Hydrochloride.

The purpose of this work is to explore the effects of novel absorption enhancers on the nasal absorption of nalmefene hydrochloride (NMF). First, the influence of absorption enhancers with different concentrations and types and drug concentrations on the nasal absorption of NMF was investigated in vivo in rats. The absorption enhancers studied include n-dodecyl-β-D-maltoside (DDM), hydroxypropyl-β-cyclodextrin (HP-β-CD), and polyethylene glycol (15)-hydroxy Stearate (Solutol®HS15). At the same time, the in situ toad palate model and rat nasal mucosa model were used to assess the cilia toxicity. The results showed that all the absorption enhancers investigated significantly promote the nasal absorption of NMF, but with different degrees and trends. Among them, the 0.5% (w/v) DDM had the strongest enhancement effect, followed by 0.5% (w/v) Solutol®HS15, 0.25% (w/v) DDM, 0.25% (w/v) Solutol®HS15, 0.1% (w/v) Solutol®HS15, 0.1% (w/v) DDM, and 0.25% (w/v) HP-β-CD, with absolute bioavailability of 76.49%, 72.14%, 71.00%, 69.46%, 60.41%, 59.42%, and 55.18%, respectively. All absorption enhancers exhibited good safety profiles in nasal ciliary toxicity tests. From the perspective of enhancing effect and safety, we considered DDM to be a promising nasal absorption enhancer. And in addition to DDM, Solutol®HS15 can also promote intranasal absorption of NMF, which will provide another option for the development of nalmefene hydrochloride nasal spray.

Epithelial transport of Noscapine across cell monolayer and influence of absorption enhancers on in vitro permeation and bioavailability: implications for intestinal absorption

The purpose of this study was to investigate the permeation of Noscapine (Nos) across the Caco-2 and Madin–Darby canine kidney (MDCK) cell monolayers and to evaluate the influence of absorption enhancers on in vitro and in vivo absorption of Nos. The bidirectional transport of Nos was studied in Caco-2 and MDCK cell monolayers at pH 5.0–7.8. The effect of 0.5% w/v chitosan (CH) or Captisol (CP) on Nos permeability was investigated at pH 5.0 and 5.8. The effect of 1–5% w/v of CP on oral bioavailability of Nos (150 mg/kg) was evaluated in Sprague–Dawley rats. The effective permeability coefficients (Peff) of Nos across Caco-2 and MDCK cell monolayers was found to be in the order of pH 5.0 > 5.8 > 6.8 > 7.8. The efflux ratios of Peff < 2 demonstrated that active efflux does not limit the absorption of Nos. The use of CH or CP have shown significant (***, p < 0.001) enhancement in Peff of Nos across cell monolayer compared with the control group. The CP (1–5% w/v) based Nos formulations resulted in significant (***, p < 0.001) increase in the bioavailability of Nos compared with Nos solution. The use of CP represents viable approach for enhancing the oral bioavailability of Nos and reducing the required dose.

Rheological investigation and its correlation with permeability coefficient of drug loaded carbopol gel: influence of absorption enhancers

Context: The present study was planned to investigate the effect of absorption enhancers on the microstructure of Losartan potassium gel and hence its influence on the diffusion of Losartan potassium across nasal mucosa.Method: Losartan potassium loaded carbopol gel (1% w/v) with and without absorption enhancers was prepared. Polyethylene glycol (PEG) 4000 and ethanol were used as absorption enhancers. Microstructural elucidation of prepared gels was done using shear rheology. Ex vivo drug release studies were performed on the prepared gels.Results: It was observed that the absorption enhancers PEG 4000 and ethanol altered the gel microstructure. The prepared gels were viscoelastic in nature suggesting their suitability for topical application. Permeability coefficient of Losartan potassium loaded into gels was found to be inversely proportional to the storage modulus. Thus increase in storage modulus lead to slow drug diffusion.Conclusion: The current study emphasizes on the fact that selection of polymeric carrier for nasal drug delivery and/or absorption enhancer strongly influence the microstructure of the gel and hence the pharmaceutical performance of the formulation.

Ex vivo and in vivo diffusion of ropivacaine through spinal meninges: Influence of absorption enhancers

Following epidural administration, cerebrospinal fluid bioavailability of local anesthetics is low, one major limiting factor being diffusion across the arachnoid mater barrier. The aim of this study was to evaluate the influence of absorption enhancers on the meningeal permeability of epidurally administered ropivacaine. Five enhancers known for their ability to increase drug permeability via transcellular and/or paracellular pathways, i.e. palmitoyl carnitine, ethylenediaminetetraacetic acid, sodium caprate, dodecylphosphocholine and pentylglycerol, were tested ex vivo on fresh specimen of meninges removed from cervical to lumbar level of rabbit spine following laminectomy and placed in diffusion chambers. Among them, sodium caprate lead to the best permeability improvement for both marker and drug (440% and 112% for mannitol and ropivacaine, respectively) and was therefore selected for in vivo study in a sheep model using microdialysis technique to evaluate epidural and intrathecal ropivacaine concentrations following epidural administration. Resulting dialysate and plasma concentrations were used to calculate pharmacokinetic parameters. Following sodium caprate pre-treatment, ropivacaine intrathecal maximal concentration (Cmax) was 1.6 times higher (78±16μgml−1 vs 129±26μgml−1, p<0.05) but the influence of the absorption enhancer was only effective the first 30min following ropivacaine injection, as seen with the significantly increase of intrathecal AUC0–30min (1629±437μgminml−1 vs 2477±559μgminml−1, p<0.05) resulting in a bioavailable fraction 130% higher 30min after ropivavaine administration. Co-administration of local anesthetics with sodium caprate seems to allow a transient and reversible improvement of transmeningeal passage into intrathecal space.

Influence of absorption enhancers on the pharmacokinetic properties of non-oral β-lactam-cefpirom using the rabbit (Chinchilla) in vivo model

The oral application is the application of the first choice for drug administration. A lot of drugs exhibit relatively low bioavailability. This may be caused by binding of the drug in the gastro-intestinal tract, by poor penetration of the intestinal mucose or by highly hydrophilic properties. Therefore, problem drugs were only used for i.v. administration (intravenously) or for i.m. administration (intramuscularly). In the present study, cefpirom was investigated as a model substance. Cefpirom (Cp) is a semi-synthetic amino-2-thiazolyl-methoxyimino cephalosporin. It exhibits highly hydrophilic properties ( P ow = 0.02 ± 0.01) and a very low bioavailability (AUC = 524 ± 403 μg min/ml). It was only applied i.v. or i.m. In this work, the influence of absorption enhancers (aggregation and ion-pair formation) on the bioavailability and on the hydrophilic properties of Cp was investigated. The bioavailability of cefpirom was improved through the combination with absorption enhancers (hexadecyldimethylbenzylammonium chloride, BAC; hexylsalicylic acid, HSA). The absolute bioavailability of the Cp combination with absorption enhancers was 21 times larger for BAC and 15 times larger for HSA than in the case when Cp was used alone.

The influence of absorption enhancers on nasal absorption of acyclovir

The objective of this work was to increase the nasal absorption of acyclovir by using absorption enhancers. Acyclovir was selected as a model drug. A rat in situ nasal perfusion technique was utilized in the investigation to examine the rate and extent of absorption of acyclovir. In vitro enzymatic drug degradation study was carried out with rat nasal washings. Various experimental conditions such as nasal perfusion rate, pH of the perfusion medium and concentrations of absorption enhancers such as sodium deoxycholate, hydroxypropyl β-cyclodextrin, sodium caprate, sodium tauroglycocholate and EDTA were optimized. Nasal absorption of acyclovir was pH dependent. Initial absorption rate constants were determined by the plot of log% remaining amount of drug in perfusate vs time. It was found maximum at pH 7.4 and decreased at lower and higher pH conditions. In in vitro enzymatic degradation study, no measurable degradation was observed during first week. The extent of drug absorption was increased via absorption enhancers. In vivo studies were carried out for the optimized formulation in rabbits and the pharmacokinetics parameters of nasal solution were compared with oral solution. Hydroxypropyl β-cyclodextrin appeared to be more effective for enhancing the nasal absorption of acyclovir than the other absorption enhancers. The order of increasing absorption of acyclovir caused by the enhancers was hydroxypropyl β-cyclodextrin>sodium deoxycholate>sodium caprate>sodium tauroglycocholate>EDTA.

Validation of Animal Experiments on Ciliary Function In Vitro. II. The Influence of Absorption Enhancers, Preservatives and Physiologic Saline

Ciliary beat frequency (CBF) is one of the most important parameters of mucociliary clearance. Previously, we demonstrated that mucosa from chicken embryo trachea is a good substitute for human ciliated epithelium to study the effects on CBF of substances that are used clinically. In this study, we examined the effect on CBF of four excipients for nasal drug formulations: the absorption enhancers methylated

Influence of absorption enhancers (bile salts) and the preservative (benzalkonium chloride) on mucociliary function and permeation barrier function in rabbit tracheas

Effects of bile salts and benzalkonium chloride on the ciliary beat activity (frequency) and the mucociliary transport rate of tracheas, and permeabilities of 6-carboxyfluorescein (6-CF; M w 376) and FITC-dextrans (FD-4; M w 4300) as hydrophilic compounds through trachea were investigated for intratracheal delivery of drugs. Ciliary beat activity was measured by an in vitro photoelectric method by using excised rabbit tracheas. Transport rate was determined by an in vivo endoscopic method in rabbit tracheas. Permeation test was carried out by using excised rabbit tracheas. The ciliary beat activities and mucociliary transport rates were not significantly affected by 1, 10 and 20 mM sodium glycocholate, while they were significantly decreased by 1 and 10 mM sodium taurodeoxycholate and immediately halted after application of 20 mM taurodeoxycholate. They were not significantly affected by 0.02% of benzalkonium chloride, whereas they were completely halted by 0.05% of benzalkonium chloride. The apparent permeability coefficients ( P app) of 6-CF and FD-4 were 2.35×10 −7 and 2.22×10 −8 cm/s, respectively. One mmol of glycocholate did not significantly increase the P app of 6-CF and FD-4, while, 10 mM of glycocholate and 1 and 10 mM of taurodeoxycholate significantly increased the P app. Benzalkonium chloride (0.01%) did not significantly increase the P app of 6-CF, whereas 0.03% significantly increased the P app of 6-CF. Benzalkonium chloride (0.01 and 0.03%) slightly increased the P app of FD-4. Therefore, sodium glycocholate may be a safe and useful absorption enhancer for intratracheal delivery of drugs.

The influence of absorption enhancers on intranasal insulin absorption in normal and diabetic subjects

The bioavailability of intranasally administered insulin in humans is very low, because insulin is a high molecular weight and hydrophilic substance. In healthy volunteers and diabetes patients some absorption enhancers proved to be very effective, including the bile salts sodium deoxycholate and glycocholate, sodium taurodihydrofusidate (STDHF), laureth-9 and didecanoyl- l-α-phosphatidylcholine (DDPC). Several studies reported an insulin bioavailability in the order of 5–10%. However, some of these absorption enhancers may be harmful for nasal epithelial membranes, because in vitro studies showed morphological damage and severe inhibition of nasal ciliary movement. In vivo, laureth-9 and sodium deoxycholate are associated with nasal irritation, and STDHF leads to painful stinging and lacrimation. Cyclodextrins, especially dimethylated β-cyclodextrin (DMβCD), improve the nasal absorption of insulin in rats. This compound is relatively non-toxic, as has been shown in various studies concerning its effect on nasal epithelial tissue. Nasal administration of liquid insulin-DMβCD solution in rats results in an almost complete insulin absorption. In contrast, experiments in rabbits and man with the same formulation show no nasal insulin absorption. However, the nasal administration of a lyophilized insulin-DMβCD powder formulation results in a rapid nasal insulin absorption with a peak level reached after about 10 min. In diabetic patients the mean absolute bioavailability of insulin with this formulation was 5.1%. Only a slight initial itch was reported. Rapid absorption of intranasally administered insulin provides a pharmacokinetic profile similar to intravenous insulin and the postprandial endogenous insulin secretion by the pancreas. Therefore, its potential may be considered as an adjunct to subcutaneous treatment. Although the results so far with a few absorption enhancers are encouraging, the nasal insulin bioavailability is very low and the long-term safety of nasal insulin therapy has to be proven. Therefore, an intranasal insulin formulation is still far away from reaching the market.