Enhanced bioavailability of exemestane via proliposomes based transdermal delivery

Exemestane, a novel steroidal aromatase inactivator used in the treatment of advanced breast cancer has limited bioavailability (42%) due to poor solubility, extensive first-pass metabolism, and also the absorption is dependent on formulation type and food. The present study is aimed to evaluate the feasibility of proliposomes for transdermal delivery of exemestane. The prepared proliposomes were characterized for size, zeta potential, and entrapment efficiency. The size of the vesicles was found to be between 440 and 700 nm with high entrapment efficiency for the formulation containing greater amounts of phosphatidylcholine. Differential scanning calorimetry and Fourier transform infrared studies were performed to understand the phase transition behavior and mechanism for skin permeation, respectively. The drug release across cellophane membrane follows zero-order kinetics by diffusion. Ex vivo permeation enhancement assessed from flux, permeability coefficient, and enhancement ratio were significantly higher for proliposome gels compared with control. A significant improvement in the bioavailability (2.4-fold) was observed from optimized proliposome gel compared with control (oral suspension). The stability data reveal that the formulations are more stable when stored at 4°C. In conclusion, proliposomal gels offer potential and prove to be efficient carriers for improved and sustained transdermal delivery of exemestane.     

Improving drug delivery from medical nebulizers: the effects of increased nebulizer flow rates and reservoirs.

Drug delivery from jet nebulizers can be considered in terms of the dose inhaled and the respirability of that dose. It is proposed that dose respirability and dose per breath can be controlled through specification of the driving gas flowrate, and that the dose inhaled per breath can also be increased through the use of nebulizer reservoirs. When a Hudson Micromist nebulizer was used and assessments of respirability were made utilizing phase Doppler interferometry, it was noted that the portion of the spray mass in droplet sizes of 相似文献   

Ultrasound-mediated drug delivery by gas bubbles generated from a chemical reaction

Highly echogenic and ultrasound-responsive microbubbles such as nitrogen and perfluorocarbons have been exploited as ultrasound-mediated drug carriers. Here, we propose an innovative method for drug delivery using microbubbles generated from a chemical reaction. In a novel drug delivery system, luminol encapsulated in folate-conjugated bovine serum albumin nanoparticles (Fol-BSAN) can generate nitrogen gas (N₂) by chemical reaction when it reacts with hydrogen peroxide (H₂O₂), one of reactive oxygen species (ROS). ROS plays an important role in the initiation and progression of cancer and elevated ROS have been observed in cancer cells both in vitro and in vivo. High-intensity focussed ultrasound (HIFU) is used to burst the N₂ microbubbles, causing site-specific delivery of anticancer drugs such as methotrexate. In this research, the drug delivery system was optimised by using water-soluble luminol and Mobil Composition of Matter-41 (MCM-41), a mesoporous material, so that the delivery system was sensitive to micromolar concentrations of H₂O₂. HIFU increased the drug release from Fol-BSAN by 52.9?±?2.9% in 10?minutes. The cytotoxicity of methotrexate was enhanced when methotrexate is delivered to MDA-MB-231, a metastatic human breast cancer cell line, using Fol-BSAN with HIFU. We anticipate numerous applications of chemically generated microbubbles for ultrasound-mediated drug delivery.     

A novel method of characterizing medicinal drug aerosols generated from pulmonary drug delivery devices

A novel method for analyzing electromechanical properties (e.g., size, electrostatic charge, polarity) of therapeutic aerosols produced by four different commercially available pressurized metered dose inhalers (pMDIs), including Albuterol?, Atrovent?, Qvar?, and Ventolin?, is presented. Respiratory drug particles aerosolized from pulmonary drug delivery devices may not only have different aerodynamic particle size distributions but also electrostatic charge distributions. The interactive effects of these two electromechanical properties on regional deposition of inhaled aerosols in the lung airway have been acknowledged by the investigators of aerosol medicine research, which requires precise quantification for analytical perspective. Experimental studies using a multi-stage electrical low pressure impactor (ELPI) reported the net charge (q(+) or q(-)) and aerodynamic diameter (d(a)) of the pMDIs. However, the ELPI has a limitation of providing the net charge of all particles deposited on its impaction stage, not for each particle in real time. To resolve this issue, this study reports the application of an electronic single-particle aerodynamic relaxation time (ESPART) analyzer, which operates on the principle of laser Doppler velocimetry to measure simultaneously d(a), q(+), and q(-) (charge magnitude and polarity) on a single particle basis and in real time. Aerosol particles from all drug delivery devices were found to not only have different size and charge distributions but they also varied in their polarities. The drug aerosols cloud emitted by Albuterol? and Ventolin? were determined to be electropositive, while Atrovent? and Qvar? were electronegative. Count and mass distributions were reproducible for all pMDIs. In conclusion, the ESPART provided more detailed charge information about the pMDI aerosol particles.     

Prodrug strategy for enhancing drug delivery via skin

Skin as a route for drug delivery has been extensively investigated. However, because of the predominant barrier function of stratum corneum in skin, the clinical application is limited. One strategy to solve this problem of drug permeation via skin is the use of prodrugs. Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to its parent active drug. Prodrugs can enhance dermal/transdermal drug delivery via different mechanisms, including increased skin partitioning, increased aqueous solubility, and reduced crystallization, etc. Besides the prodrug itself, the optimization of vehicle is important as well. The prodrug partitioning between skin and vehicle as well as prodrug-vehicle interaction may influence the enhancing efficacy on skin permeation. This review explores the synthesis and enhancing mechanisms of prodrugs for topical drug delivery. The prodrugs categorized by the therapeutic use of the parent drugs, including anticancer drugs, analgesics, anti-inflammatory drugs and vitamins, are systemically introduced in this review.     

A mechanism for improved talc pleurodesis via foam delivery

Talcum powder is recognized as the leading drug for pleurodesis, a treatment of choice for malignant pleural effusions. Recently, it was shown that hydrogel foam delivery systems significantly enhanced the number of adhesions between the chest wall and the lung in a New Zealand rabbit model due to the sol-gel transition. However, many questions still remain regarding the cause of improved efficacy, such as: (1) Would only hydrogel foams improve the efficacy of talc pleurodesis? (2) Is it possible to achieve the same efficacy of hydrogels using non-hydrogel foams? 3) What are the physicochemical properties that can be correlated to the efficacy of talc pleurodesis? In this study, we use non-hydrogel foam formulations to determine the efficacy of pleurodesis. Foam stability and rheology of the formulations were correlated to adhesion formation. The results clearly suggest a correlation of pleurodesis efficacy to the viscosity and modulus of the foam delivery system.     

Cytosolic delivery via escape from the endosome using emulsion droplets and ultrasound

Vaporizing emulsion droplets may aid in endosomal rupture as a drug delivery route to the cytosol. Upon insonation, emulsion droplets formed from perfluorocarbon liquids may vaporize with sufficient expansion to disrupt liposomal or endosomal membranes. Emulsion droplets of perfluorohexane (PFC6) or perfluoropentane (PFC5) were prepared as free droplets in calcein or as droplets encapsulated within liposomes containing calcein. Folate-stimulated endocytosis created an experimental model, wherein calcein was self-quenched until released from the vesicles. Upon release, calcein was diluted below its self-quenching concentration and its release quantified by fluorescence. In this experimental model, folated emulsions or folated eLiposomes were incubated with folate-starved HeLa cells. Samples were exposed to two seconds of 20-kHz ultrasound (US) at 1?W/cm². Fluorescence microscopy identified released intracellular calcein. Upon insonation, both free emulsion samples and eLiposome samples produced calcein release to the cytosol. Calcein fluorescence was more intense in samples containing PFC5 compared to PFC6. Insonation of samples without emulsion droplets produced no cytosolic delivery. Likewise, cells that took up emulsion droplets but were not exposed to US did not exhibit fluorescence throughout the cell. These results suggest that vaporizing emulsion droplets are internalized into the cells and can produce endosomal escape of a therapeutic payload.     

Brain-specific delivery of rifampin from lactyl stearate-coupled liposomes via monocarboxylic acid transporters

Background

The blood-brain barrier (BBB) is an obstacle for pharmacologists wishing to find treatments for patients with brain disorders. The BBB restricts the uptake of many valuable hydrophilic drugs and limits their efficacy because of the presence of tight junctions, a high metabolic capacity, low pinocytic vesicular traffic, and efficient efflux mechanisms.

Aim

The present study aimed to characterize lactyl stearate-coupled liposomes and their potential for the brain targeting of rifampin (rifampicin).

Method

A liposomal delivery system was prepared for achieving the brain-targeted delivery of rifampin in 21 albino rats utilizing the monocarboxylic acid transport system. Liposomes were prepared by the cast-film method using phosphatidylcholine and cholesterol. Similarly, lactyl stearate-coupled liposomal systems were prepared by casting lactyl stearate film with lipids. These liposomal formulations were characterized for entrapment efficiency, vesicle size, in vitro drug release (using dialysis membrane), and in vivo drug accumulation in various tissues.

Results

Coupling of lactyl stearate to liposomes had a profound influence on entrapment efficiency. Entrapment efficiency was reduced from 41.28 ± 2.02% in uncoupled liposomes to 34.23 ± 1.60% in coupled liposomes. The vesicle size was increased after coupling with lactyl stearate. The in vitro drug release for the uncoupled formulation LIPO-3 was 62.9 ± 3.01% after 24 hours, whereas that of the coupled formulation LIPO-3-Ls-III was 44.5 ± 2.09%. The percentage of rifampin dose recovered from the brain following administration of lactyl stearate-coupled liposomes to albino rats at different time intervals was about 6–8 times higher than with uncoupled liposomes and about 10–12 times higher than with the plain drug solution.

Conclusion

Lactyl stearate-coupled liposomes were better localized within the brain compared to uncoupled liposomes. Lactyl stearate-coupled liposomes could be an excellent carrier system for brain targeting of the hydrophilic drug rifampin.     

Lasers as an approach for promoting drug delivery via skin

Introduction: Using lasers can be an effective drug permeation-enhancement approach for facilitating drug delivery into or across the skin. The controlled disruption and ablation of the stratum corneum (SC), the predominant barrier for drug delivery, is achieved by the use of lasers. The possible mechanisms of laser-assisted drug permeation are the direct ablation of the skin barrier, optical breakdown by a photomechanical wave and a photothermal effect. It has been demonstrated that ablative approaches for enhancing drug transport provide some advantages, including increased bioavailability, fast treatment time, quick recovery of SC integrity and the fact that skin surface contact is not needed. In recent years, the concept of using laser techniques to treat the skin has attracted increasing attention.

Areas covered: This review describes recent developments in using nonablative and ablative lasers for drug absorption enhancement. This review systematically introduces the concepts and enhancement mechanisms of lasers, highlighting the potential of this technique for greatly increasing drug absorption via the skin. Lasers with different wavelengths and types are employed to increase drug permeation. These include the ruby laser, the erbium:yttrium-gallium-garnet laser, the neodymium-doped yttrium-aluminum-garnet laser and the CO₂ laser. Fractional modality is a novel concept for promoting topical/transdermal drug delivery. The laser is useful in enhancing the permeation of a wide variety of permeants, such as small-molecule drugs, macromolecules and nanoparticles.

Expert opinion: This potential use of the laser affords a new treatment for topical/transdermal application with significant efficacy. Further studies using a large group of humans or patients are needed to confirm and clarify the findings in animal studies. Although the laser fluence or output energy used for enhancing drug absorption is much lower than for treatment of skin disorders and rejuvenation, the safety of using lasers is still an issue. Caution should be used in optimizing the feasible conditions of the lasers in balancing the effectiveness of permeation enhancement and skin damage.     

Transporting carriers for intracellular targeting delivery via non-endocytic uptake pathways

Abstract

To develop novel therapies for clinical treatments, it increasingly depends on sophisticated delivery systems that facilitate the drugs entry into targeting cells. Profound understanding of cellular uptake routes for transporting carriers promotes the optimization of performance in drug delivery systems. Although endocytic pathway is the most important part of cellular uptake routes for many delivery systems, it suffers the trouble of enzymatic degradation of transporting carriers trapped in endosomes/lysosomes. Therefore, it is desirable to develop alternative transporting methods for delivery systems via non-endocytic pathways to achieve more effective intracellular delivery. In this review, we summarize the literature exploring transporting carriers that mediate intracellular delivery via non-endocytic pathways to present the current research status in this field. Cell-penetrating peptides, pH (low) insertion peptides, and nanoparticles are categorized to exhibit their ability to directly transport various cargos into cytoplasm via non-endocytic uptake in different cell lines. It is hoped that this review can spur the interesting on development of drug delivery systems via non-endocytic uptake pathway.     

Formulations for protecting the probiotic Saccharomyces boulardii from degradation in acidic condition

Saccharomyces boulardii is a nonpathogenic yeast with proven health benefits, some of them depending on its viability. However, the living yeast is sensitive to environmental conditions and its viability is less than 1% in the faeces after oral administration. Therefore, we assessed the survival conditions of S. boulardii in aqueous suspension and in its freeze-dried form and we formulated microspheres with the former and tablets with the latter in order to preserve the viability of the probiotic. While the viability of the yeast in aqueous suspension could be maintained for one year at -20 degrees C and +5 degrees C, increasing the temperature led to almost total mortality within 14 d at +40 degrees C and 4 d at +60 degrees C. The viability of the freeze-dried yeast was preserved for one year at +25 degrees C without moisture. With 75% relative humidity, the mortality was significant at 28 d at +25 degrees C and almost total within 1 d at +60 degrees C. In vitro, whereas less than 1% of non-encapsulated or non-tabletted S. boulardii survived after 120 min at pH 1.1, both formulations in microspheres and direct compression enabled to protect the yeast from degradation in HCl and to release it viable at pH 6.8. However, despite a similar release profile from both dosage forms, the compression led to a significant decrease in the viability of the freeze-dried yeast. In conclusion, although both formulations are efficient in protecting S. boulardii in acidic condition, microspheres provide a higher entrapment efficiency and a faster release of the viable probiotic in intestinal condition than matrix tablets.     

In vitro evaluation of paclitaxel coatings for delivery via drug-coated balloons

Lately, drug-coated balloons have been introduced in interventional cardiology as an approach to treat occluded blood vessel. They were developed for the rapid transfer of antiproliferative drugs during the angioplasty procedure in stenosed vessels with the intent to reduce the risk of restenosis. In this study five different paclitaxel (PTX) balloon coatings were tested in vitro in order to examine how solvents and additives influence coating stability and drug transfer rates. PTX-coated balloons were advanced through a guiding catheter and a simulated coronary artery pathway under perfusion and were then inflated in a hydrogel acceptor compartment. The fractions transferred to the gel, remaining on the balloon and the PTX lost in the simulated coronary pathway were then analysed. The results obtained suggest that the solvent used for the coating process strongly influences the surface structure and the stability of the coating.Ethanol/water and acetone based PTX coatings showed the lowest drug transfer rates to the simulated vessel wall (both <1%) due to their high drug losses during the prior passage through the coronary artery model (more than 95%). Balloons coated with PTX from ethyl acetate-solutions showed smaller drug loss (83% ± 9%), but most of the remaining PTX was not transferred (mean balloon residue approximately 15%).Beside the solvent, the use of additives seemed to have a great impact on transfer properties. The balloon pre-treatment with a crosslinked polyvinylpyrrolidone (PVP) film was able to increase the PTX transfer rate from less than 1% (without PVP) to approximately 6%. The best results in this study were obtained for balloon coatings with commercially available SeQuent© Please balloons containing the contrast agent iopromide. For this formulation drug transfer rates of approximately 17% were determined. Fluorescence microscopic imaging could visualize the particulate transfer of labelled PTX from the balloon surface during dilatation. The findings of this study underline the importance of drug adhesion and coating stability for the efficiency of PTX transfer.     

Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery

Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC–MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports.     

Oral transmucosal delivery of domperidone from immediate release films produced via hot-melt extrusion technology

The objective of the study was to prepare and characterize the domperidone (DOM) hot-melt extruded (HME) buccal films by both in vitro and in vivo techniques. The HME film formulations contained PEO N10 and/or its combination with HPMC E5 LV or Eudragit RL100 as polymeric carriers, and PEG3350 as a plasticizer. The blends were co-processed at a screw speed of 50 rpm with the barrel temperatures ranging from 120–160°C utilizing a bench top co-rotating twin-screw hot-melt extruder using a transverse-slit die. The HME films were evaluated for drug content, drug excipient interaction, in vitro drug release, mechanical properties, in vivo residence time, in vitro bioadhesion, swelling and erosion, ex vivo permeation from HME films and the selected optimal formulation was subjected for bioavailability studies in healthy human volunteers. The extruded films demonstrated no drug excipient interaction and excellent content uniformity. The selected HME film formulation (DOM2) exhibited a tensile strength (0.72 Kg/mm²), elongation at break (28.4% mm²), in vivo residence time (120 min), peak detachment force (1.55 N), work of adhesion (1.49 mJ), swelling index (210.2%), erosion (10.5%) and in vitro drug release of 84.8% in 2 h. Bioavailability from the optimized HME buccal films was 1.5 times higher than the oral dosage form and the results showed statistically significant (p < 0.05) difference. The ex vivo–in vivo correlation was found to have biphasic pattern and followed type A correlation. The results indicate that HME is a viable technique for the preparation of DOM buccal-adhesive films with improved bioavailability characteristics.     

Targeted drug delivery to the central nervous system via phosphonate derivatives (anionic delivery system for testosterone)

An anionic chemical delivery system (aCDS) has been developed and applied to deliver testosterone (T) to the central nervous system (CNS). The delivery of a target compound is achieved through the use of a specific targetor moiety which is an (acyloxy)alkyl-phosphonate-type functional group. The T-aCDS readily penetrates biological membranes by passive transport due to its increased lipophilicity and enters the target organ. Hydrolytic cleavage by esterases provides a negatively charged, hydrophilic intermediate phosphonate compound (TP-), which is "locked in" the CNS and should provide sustained, site-specific release of the drug. In vitro and in vivo investigations in rats showed that methyl-pivaloyloxymethyl-17-testosterylphosphonate (T-aCDS) might function as an anionic chemical delivery system of testosterone. The concentration of T-aCDS decreased fairly rapidly in vitro. The half-lives (t1/2) in different organs are as follows: blood 4.48 min (r = 0.9388), lung 5.53 min (r = 0.9661), liver 2.82 min (r = 0.9498), and brain 7.37 min (r = 0.9972). Simultaneously with the disappearance of T-aCDS, testosterone-phosphonate (TP-) appeared as a main metabolite in increasing concentration. In vivo evaluations (tail vein 11.3 mg/kg in DMSO) found maximum T-aCDS brain levels 5-10 min after administration; they fell under the borderline of detectability (< 0.1 microgram/g) after 60 min. Maximum concentration of the decomposition product (TP-) was obtained at 30 min after administration; it did not decrease significantly during the study. Even if the phosphonate derivative of the secondary, hindered hydroxyl group in this product was fairly resistant to phosphorolytic attack, the design principle can work for other compounds.     

Pharmacokinetics and pharmacodynamics of sterylglucoside-modified liposomes for levonorgestrel delivery via nasal route

For emergency contraceptive, the rapid delivery of levonorgestrel (LNG) to plasma is desirable, furthermore, a sustained delivery of LNG along with rapid absorption will be necessary. The pharmacokinetics and pharmacodynamics of LNG entrapped in different kinds of liposome formulations via nasal administration in rats were evaluated and compared with LNG suspension via the oral route. The relative bioavailabilities of these liposome formulations via nasal administration were 100% or higher than 100%. The C_max and T_max values of sterylglucoside (SG) and chitosan-contained formulations by nasal administration were 416.84 ng/mL and 1.02 hr, 227.97 ng/mL and 2.02 hr, respectively, compared with that of 334.94 ng/mL and 1.89 hr of oral suspension. Fully 100% contraception was observed for all the formulations. SG could promote the absorption of LNG via the nasal route and may provide a rapid onset of action of LNG for emergency contraception. Chitosan could retain LNG in the nasal cavity for long contact time to sustain delivery of LNG. The rapid onset and sustained delivery of LNG can be achieved via the nasal route using liposomes as the vehicle.     

Preparation of honokiol-loaded chitosan microparticles via spray-drying method intended for pulmonary delivery

It has been demonstrated that spray-drying is a powerful method to prepare dry powders for pulmonary delivery. This paper prepared dispersible dry powders based on chitosan and mannitol containing honokiol nanoparticles as model drug. The results showed that the prepared microparticles are almost spherical and have appropriate aerodynamic properties for pulmonary delivery (aerodynamic diameters was between 2.8–3.3 μm and tapped density ranging from 0.14–0.?18?g/cm³). Moreover, surface morphology and aerodynamic properties of the powders were strongly affected by the content of mannitol. Fourier transform infra-red (FTIR) spectrum of powders indicated that the honokiol nanoparticles were successfully incorporated into microparticles. In vitro drug release profile was also observed. The content of mannitol in powders significantly influenced the release rate of honokiol from matrices.     

Recent approaches of lipid-based delivery system for lymphatic targeting via oral route

Abstract

Lymphatic system is a key target in research field due to its distinctive makeup and huge contributing functions within the body. Intestinal lymphatic drug transport (chylomicron pathway) is intensely described in research field till date because it is considered to be the best for improving oral drug delivery by avoiding first pass metabolism. The lymphatic imaging techniques and potential therapeutic candidates are engaged for evaluating disease states and overcoming these conditions. The novel drug delivery systems such as self-microemulsifying drug delivery system, nanoparticles, liposomes, nano-lipid carriers, solid lipid carriers are employed for delivering drugs through lymphatic system via various routes such as subcutaneous route, intraperitoneal route, pulmonary route, gastric sub-mucosal injection, intrapleural and intradermal. Among these colloidal particles, lipid-based delivery system is considered to be the best for lymphatic delivery. From the last few decades, mesenteric lymph duct cannulation and thoracic lymph duct cannulation are followed to assess lymphatic uptake of drugs. Due to their limitations, chylomicrons inhibitors and in-vitro models are employed, i.e. lipolysis model and permeability model. Currently, research on this topic still continues and drainage system used to deliver the drugs against lymphatic disease as well as targeting other organs by modulating the chylomicron pathway.