Dissolving microneedle-based intradermal delivery of interferon-α-2b

Abstract

The dermal and transdermal delivery of protein pharmaceuticals faces enormous challenges, and at the same time, has very significant potential for the non-invasive treatment of both localized and systemic diseases. To demonstrate the pharmaceutical usefulness of dissolving microneedles (MNs) containing interferon-α-2b (IFN), IFN MNs were prepared using a new method. IFN were encapsulated in MNs with dose from 4.94?±?0.64 to 23.79?±?2.48?μg, and in vitro release test showed the efficiency reached 49.2%. After percutaneous administration of IFN MNs to rats, serum IFN levels were measured for 12?h. The peak serum IFN level, maximum drug concentration (C_max), and the time to reach maximum concentration (T_max), were 11.58?±?ng/ml and 40 min, respectively, for high-dose MNs group. The area under the curve (AUC) of MNs group was 28.85?ng·h/ml, while intramuscular injection (IM) group with equal dose was 31.17?ng·h/ml. Immunogenicity analysis showed the anti-IFN antibody got back to normal level at ninth week, and there was no difference between male and female rats. IFN MNs showed good stability for 2 months and no damage to the administered rats’ skin. The results demonstrated the IFN MNs have a great potential to provide an alternative to IM.     

Sol–gel processing of drug delivery zirconia/polycaprolactone hybrid materials

Poly(є-caprolactone) (PCL 6, 12 and 24 wt%) and zirconium (ZrO₂) organic–inorganic hybrid materials have been synthesized by the sol–gel method from a multicomponent solution containing zirconium propoxide [Zr(OC₂H₇)₄], poly(ε-caprolactone) (PCL), water, chloroform (CHCl₃). Sodium ampicillin was incorporate in the hybrid materials to verify the effect as local controlled drug delivery system. The structure of interpenetrating network is realized by hydrogen bonds between Zr-OH group (H donator) in the sol–gel intermediate species and carboxylic group (H-acceptor) in the repeating units of the polymer. The presence of hydrogen bonds between organic/inorganic components of the hybrid material was proved by FTIR analysis. The morphology of the hybrid material was studied by scanning electron microscope (SEM). The structure of a molecular level dispersion has been disclosed by atomic force microscope (AFM), pore size distribution and surface measurements. The bioactivity of the synthesized hybrid material has been showed by the formation of a layer of hydroxyapatite on the surface of PCL/ZrO₂ samples soaked in a fluid simulating the composition of the human blood plasma. Release kinetics in a simulate body fluid (SBF) have been subsequently investigate. The amount of sodium ampicillin released has been detected by UV–VIS spectroscopy and SEM. The release kinetics seems to occur in more than one stage. HPLC analysis has also been taken to ensure the integrity of ampicillin after the synthetic treatment.     

Polymorphism of 17-β estradiol in a transdermal drug delivery system

The inclusions in a typical transdermal drug delivery system (TDS) containing estradiol drug were characterized using microscopic, spectroscopic and thermal analytical techniques. Optical and scanning electron microcscopy were used to determine the locations and morphologies of the crystals in the matrix. Two different types of crystals randomly distributed laterally inside the patch were observed. Solid aggregates were found surrounding needle-like inclusions. Optical imaging through the thickness of the patch and SEM sections of the patch revealed that these inclusions were found to occupy a single layer inside the adhesive matrix. No inclusions were observed either in the backing–matrix interface or the matrix–liner interface. The inclusions exhibited a wide range of sizes. The thickness of the crystals as determined by SEM ranged from 10–14 m. Out of the four crystal forms of estradiol, two of which are solvates (EA and EM) and the other two are anhydrous (EC and ED). Forms EC and ED did not exhibit significant differences in the spectra. Thermal analysis revealed that this was due to the highly unstable nature of ED and its tendency to either convert spontaneously to EC or occur in mixtures with it. The Raman spectrum of the aggregates in the patch showed peaks that seemed characteristic of at least two different forms of estradiol. Only one of these forms is a completely hydrogen bonded system and therefore, was concluded to be estradiol hemihydrate. A splitting of the C17–O peak at 1284 cm^{- 1} and 1294 cm^{- 1} was attributed to the existence of at least two types of crystal forms – one that exhibits hydrogen bonding and one that does not. DSC on different concentrations of estradiol in acrylic adhesive showed a clear endotherm for 14 wt % estradiol and apparent endotherms for lower concentrations. The absence of crystallization exotherms is due to the extremely slow kinetics of crystals growth in the polymeric patch.     

Synthesis of a “clickable” Angiopep-conjugated p-coumaric acid for brain-targeted delivery

Overexpression of free radicals in the brain is emerging as important markers in the etiology of neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, and stroke. Numerous antioxidants with protective effect on neuronal injuries under oxidative stress are often limited to penetrate the blood–brain barrier (BBB). Angiopep-2 is the ligand of low-density lipoprotein receptor-related protein expressed on the BBB possessing high transcytosis capacity and parenchymal accumulation. In this study, novel Angiopep-conjugated p-coumaric acid (3) was synthesized, using the Click chemistry, as a potential antioxidant for the protection of the brain under oxidative stress. The clickable Angiopep (3) was synthesized by Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of the terminal acetylene-modified Angiopep and azide of p-coumaric acid. The Angiopep-conjugated compound (3) showed antioxidant potency and non-cytotoxic effect toward brain endothelial cells (BECs). Obviously, the penetration and BECs protection of 3 were higher than that of the unconjugated p-coumaric acid. The results establish the bio-conjugation of antioxidant and Angiopep with enhanced protective effect on the BECs under oxidative stress. The findings provide great potential for the development of neurotherapeutics with increased brain penetration.     

Small-bore hollow waveguides for delivery of 3-µm laser radiation

Flexible hollow glass waveguides with bore diameters as small as 250 μm have been developed for 3-μm laser delivery. All the guides exhibit straight losses between 0.10 and 1.73 dB/m, and the loss increases to between 2.4 and 5.1 dB/m upon bending 1 m of the guides into 15-cm-diameter coils. This behavior is shown to depend strongly on the launch conditions and mode quality of the input beam. The waveguides are capable of efficiently delivering up to 8 W of Er:YAG laser power with proper input coupling, and they are suitable for use in both medical and industrial applications.     

PLGA–PEG–PLGA hydrogel for ocular drug delivery of dexamethasone acetate

Aim: This study aims to investigate the suitability of thermosensitive triblock polymer poly-(dl-lactic acid-co-glycolic acid) (PLGA)–polyethylene glycol (PEG)–PLGA as a matrix material for ocular delivery of dexamethasone acetate (DXA). Methods: The copolymer was synthesized and evaluated for its thermosensitive and gelation properties. DXA in situ gel-forming solution based on PLGA–PEG–PLGA copolymer of 20% (w/w) was prepared and evaluated for ocular pharmacokinetics in rabbit according to the microdialysis method, which was compared to the normal eye drop. Result: The copolymer with 20% (w/w) had a low critical solution temperature of 32°C, which is close to the surface temperature of the eye. The C_max of DXA in the anterior chamber for the PLGA–PEG–PLGA solution was 125.2 μg/mL, which is sevenfold higher than that of the eye drop, along with greater area under the concentration–time curves (AUC). Conclusion: These results suggest that the PLGA–PEG–PLGA copolymer is potential thermosensitive in situ gel-forming material for ocular drug delivery, and it may improve the bioavailability, efficacy of some eye drugs.     

Synthesis of pH-responsive triazine skeleton nano-polymer composite containing AIE group for drug delivery

We exploited a unique porous structure of the nano-covalent triazinepolymer(NCTP)containing aggregation-induced emission(AlE)group to achievecontrolled release and drug tracking in tumor acidic microenvironment.NCTP wassynthesized by the Friedel-Crafts alkylation and the McMurry coupling reaction.It notonly had strong doxorubicin(DOX)-loading capacity due to its high specific surface areaand large pore volume,but also showed the significant cumulative drug release as aresult of the pH response of triazine polymers.NCTP was induced luminescence aftermass accumulation near tumor cells.Besides,it had excellent biocompatibility andobvious antineoplastic toxicity.The results demonstrate that NCTP as a utility-type drugcarrier provides a new route for designing the multi-functional drug delivery platform.     

Preparation and characterization of marine sponge collagen nanoparticles and employment for the transdermal delivery of 17β-estradiol-hemihydrate

Background: Transdermal administration of estradiol offers advantages over oral estrogens for hormone replacement therapy regarding side effects by bypassing the hepatic presystemic metabolism. Aim: The objective of this study was to develop nanoparticles of Chondrosia reniformis sponge collagen as penetration enhancers for the transdermal drug delivery of 17β-estradiol-hemihydrate in hormone replacement therapy. Method: Collagen nanoparticles were prepared by controlled alkaline hydrolysis and characterized using atomic force microscopy and photon correlation spectroscopy. Estradiol-hemihydrate was loaded to the nanoparticles by adsorption to their surface, whereupon a drug loading up to 13.1% of sponge collagen particle mass was found. After incorporation of drug-loaded nanoparticles in a hydrogel, the estradiol transdermal delivery from the gel was compared with that from a commercial gel that did not contain nanoparticles. Results: Saliva samples in postmenopausal patients showed significantly higher estradiol levels after application of the gel with nanoparticles. The area under the curve (AUC) for estradiol time–concentration curves over 24 hours was 2.3- to 3.4-fold higher and estradiol levels 24 hours after administration of estradiol were at least twofold higher with the nanoparticle gel. Conclusions: The hydrogel with estradiol-loaded collagen nanoparticles enabled a prolonged estradiol release compared to a commercial gel and yielded a considerably enhanced estradiol absorption. Consequently, sponge collagen nanoparticles represent promising carriers for transdermal drug delivery.     

Microemulsion-based patch for transdermal delivery of huperzine A and ligustrazine phosphate in treatment of Alzheimer’s disease

The aim of the present study was to construct an innovative microemulsion-based patch for simultaneously transdermal delivery of huperzine A (HA) and ligustrazine phosphate (LP). The pseudo-ternary phase diagrams for microemulsion region were developed using oleic acid as oil, Cremophor RH40 as a surfactant, and ethanol as a cosurfactant. 1,8-cineole was added to the microemulsion as a penetration enhancer. The microemulsion-based transdermal patches were prepared by the lamination technique. The permeation studies were performed in vitro to evaluate the abilities of various microemulsions and transdermal patches to deliver HA and LP across the rat abdominal skin, showing that microemulsions increased the permeation rates of HA and LP compared with the control, and the penetration kinetics of the transdermal patch was in a zero order process. The results of the pharmacodynamic studies indicated that the transdermal combination therapy of HA and LP showed more benefits for fighting against amnesia in comparison with monotherapy. The anti-amnesic effects were also confirmed in scopolamine-induced amnesia rats after transdermal administration at multiple doses for 9 consecutive days, and the efficacy exhibited a dose-dependent manner. As a conclusion, the microemulsion-based transdermal patch containing HA and LP might provide a feasible strategy for the prevention of Alzheimer’s disease.     

Engineered microparticles based on drug–polymer coprecipitates for ocular-controlled delivery of Ciprofloxacin: influence of technological parameters

Abstract

Ciprofloxacin is a drug active against a broad spectrum of aerobic Gram-positive and Gram-negative bacteria, for the therapy of ocular infections. It requires frequent administrations owing to rapid ocular clearance and it is a good candidate for ocular controlled release formulations. The preparation of such drug release systems is still a challenge. Ionic interactions between ciprofloxacin and the polyelectrolytes chondroitin sulfate or lambda carrageenan result in coprecipitates that can act as microparticulate controlled release systems from which the drug is released after being displaced by the medium’s ions. In some formulations, Carbopol was added to improve the mucoadhesive properties. The aim of this research was the study of the influence of the technological parameters of the preparation method of coprecipitates on their particle size, with the goal of achieving particles engineered with a size suitable for the ocular administration. Technological parameters taken into account were: concentration of drug and polymer solutions utilized for the preparation of interaction products, possible use of surfactants (kind and concentration), temperature of the solutions and stirring during the process of preparation of the coprecipitates. Preliminary stability study tests were carried out to further characterize the leader formulation. Particle size in suspensions for ocular drug delivery is a critical parameter influencing the quality of the formulation. The results obtained from this study show that chondroitin sulfate coprecipitates present the best characteristics in terms of particle size suitable for ocular administration. A further improvement of the particle size characteristics has been obtained with the addition of surfactants.     

Development and in vitro–in vivo evaluation of a water-in-oil microemulsion formulation for the oral delivery of troxerutin

Objective: The main objective of this study was to develop and evaluate a W/O microemulsion formulation of troxerutin to improve its oral bioavailability.

Methods: The W/O microemulsion was optimized using a pseudo-ternary phase diagram and evaluated for physical properties. In vitro MDCK cell permeability studies were carried out to evaluate the permeability enhancement effect of microemulsion, and in vivo absorption of troxerutin microemulsion in the intestine was compared with that of solution after single-dose administration (56.7?mg/kg) in male Wistar rats.

Results: The optimal formulation consisted of lecithin, ethanol, isopropyl myristate and water (23.30/11.67/52.45/12.59 w/w) was physicochemical stable and the mean droplet size was about 50.20?nm. In vitro study, the troxerutin-loaded microemulsion showed higher intestinal membrane permeability across MDCK monolayer when compared with the control solution. The W/O microemulsion can significantly promote the intestinal absorption of troxerutin in rats in vivo, and the relative bioavailability of the microemulsion was about 205.55% compared to control solution.

Conclusion: These results suggest that novel W/O microemulsion could be used as an effective formulation for improving the oral bioavailability of troxerutin.     

Development of a nanogel formulation for transdermal delivery of tenoxicam: a pharmacokinetic–pharmacodynamic modeling approach for quantitative prediction of skin absorption

This study investigates potentials of solid lipid nanoparticles (SLN)-based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetic–pharmacodynamic (PK–PD) modeling approach for predicting concentration–time profile in skin. A 2³ factorial design was adopted to study the effect of formulation factors on SLN properties and determine the optimal formulation. SLN-gel tolerability was investigated using rabbit skin irritation test. Its anti-inflammatory activity was assessed by carrageenan-induced rat paw edema test. A published Hill model for in vitro inhibition of COX-2 enzyme was fitted to edema inhibition data. Concentration in skin was represented as a linear spline function and coefficients were estimated using non-linear regression. Uncertainty in predicted concentrations was assessed using Monte Carlo simulations. The optimized SLN was spherical vesicles (58.1?±?3.1?nm) with adequate entrapment efficiency (69.6?±?2.6%). The SLN-gel formulation was well-tolerated. It increased TNX activity and skin level by 40?±?13.5, and 227?±?116%, respectively. Average C_max and AUC_0–24 predicted by the model were 2- and 3.6-folds higher than the corresponding values computed using in vitro permeability data. SLN-gel is a safe and efficient carrier for TNX across skin in the treatment of inflammatory disorders. PK–PD modeling is a promising approach for indirect quantitation of skin deposition from PD activity data.     

Characterization and evaluation of β-glucan formulations as injectable implants for protein and peptide delivery

Context: Injectable implants are biodegradable, syringeable formulations that are injected as liquids, but form a gel inside the body due to a change in pH, ions or temperature.

Objective: To investigate the effect of polymer concentration, pH, ions and temperature on the gel formation of β-glucan, a natural cell-wall polysaccharide derived from barley, with particular emphasis on two-phase system formation after addition of dextran or PEG.

Materials and methods: Oscillation viscometry was used to evaluate the gel character by measuring flow index (N), storage (G′) and loss (G″) moduli. Two-phase systems were further characterized for hardness and syringeability using a texture analyzer. Finally, in vitro release characteristics were determined using Franz diffusion cells.

Results: Oscillation viscometry revealed that only addition of dextran or PEG resulted in distinct gel formation. This was seen by a decrease in N after polymer addition. Moreover, hardness (in g) of the gels increased significantly (p?<?0.001) from 3.65?±?0.43 to 34.30?±?8.90 (dextran) and 805.80?±?5.30 (PEG) 24?h after polymer addition. In vitro release profiles showed significantly (p?<?0.05) reduced AUC_{0–8 h}, k and percentage of drug released from two-phase systems compared to β-glucan dispersions, with the PEG system resulting in the lowest amount released over 8?h (15.1?±?1.6%).

Discussion: The unfavorable mixing enthalpy and higher water affinity of PEG resulted in the formation of a dense β-glucan gel.

Conclusion: 1.5% (w/w) β-glucan combined with PEG at a ratio of 1:3 seemed to be the most promising injectable formulation with respect to fastest gel formation, increased hardness and sustained release.     

Albumin mediated reactive oxygen species scavenging and targeted delivery of methotrexate for rheumatoid arthritis therapy

Rheumatoid arthritis(RA)is a common chronic systemic autoimmune disease.Although there are a variety of treatments for RA,the substantial clinical therapies are still limited to disease-modifying anti-rheumatic drugs(DMARD),which would induce obvious side-effect in patients after long-term administration.Herein,an uncomplicated drug-induced self-assembly strategy was proposed to fabricate enzyme-loaded albumin nanomedicine.The hydrophobic drug methotrexate(MTX)could induce self-assembly of superoxide dismutase(SOD)and human serum albumin(HSA)to form HSA-SOD-MTX nanoparticle.After intravenous injection,dual-modal imaging including fluorescence imaging or single-photon emission computed tomography(SPECT)/CT imaging exhibits high accumulation of cyanine 5.5(Cy5.5)or 125l labeled HSA-SOD-MTX nanoparticles in the joints of collagen-induced arthritis(CIA)mice.Importantly,using the synergy therapy of SOD enzyme to scavenge the reactive oxygen species(ROS)and MTX to suppress inflammation,HSA-SOD-MTX nanoparticles exhibit excellent therapeutic efficiency of RA in CIA mice compared with the other groups.Micro-CT and clinical arthritis score of RA mice further demonstrate that RA symptoms of mice treated with HSA-SOD-MTX nanoparticles is significantly relived,which was further demonstrated by the histological analysis and the inflammatory factors measurement.The synergy therapy of inflammation by MTX and SOD enzyme based on HSA-SOD-MTX nanoparticles show excellent therapeutic effects of RA without inducing obvious side effects.Therefore,our strategy may further promote the highly efficient therapy of RA using SOD enzyme to scavenge the ROS and decreasing the side-effect of MTX,which may provide the reference for clinical RA treatment.     

Characterization and evaluation of β-glucan formulations as injectable implants for protein and peptide delivery

Context: Injectable implants are biodegradable, syringeable formulations that are injected as liquids, but form a gel inside the body due to a change in pH, ions or temperature. Objective: To investigate the effect of polymer concentration, pH, ions and temperature on the gel formation of β-glucan, a natural cell-wall polysaccharide derived from barley, with particular emphasis on two-phase system formation after addition of dextran or PEG. Materials and methods: Oscillation viscometry was used to evaluate the gel character by measuring flow index (N), storage (G') and loss (G″) moduli. Two-phase systems were further characterized for hardness and syringeability using a texture analyzer. Finally, in vitro release characteristics were determined using Franz diffusion cells. Results: Oscillation viscometry revealed that only addition of dextran or PEG resulted in distinct gel formation. This was seen by a decrease in N after polymer addition. Moreover, hardness (in g) of the gels increased significantly (p?相似文献   

Design,optimization and evaluation of poly-ɛ-caprolactone (PCL) based polymeric nanoparticles for oral delivery of lopinavir

Lopinavir (LPV)-loaded poly-ε-caprolactone (PCL) nanoparticles (NPs) were prepared by emulsion solvent evaporation technique. Effects of various critical factors in preparation of loaded NPs were investigated. Box–Behnken design (BBD) was employed to optimize particle size and entrapment efficiency (EE) of loaded NPs. Optimized LPV NPs exhibited nanometeric size (195.3?nm) with high EE (93.9%). In vitro drug release study showed bi-phasic sustained release behavior of LPV from NPs. Pharmacokinetic study results in male Wistar rats indicated an increase in oral bioavailability of LPV by 4-folds after incorporation into PCL NPs. From tissue distribution studies, significant accumulation of loaded NPs in tissues like liver and spleen indicated possible involvement of lymphatic route in absorption of NPs. Mechanistic studies using rat everted gut sac model revealed endocytosis as a principal mechanism of NPs uptake. In vitro rat microsomal metabolism studies demonstrated noticeable advantage of LPV NPs by affording metabolic protection to LPV. These studies indicate usefulness of PCL NPs in enhancing oral bioavailability and improving pharmacokinetic profile of LPV.     

Supplier selection under risk of delivery failure: a decision-support model considering managers’ risk sensitivity

This paper studies the problem of supplier selection and order allocation in a retail supply chain (comprising suppliers, a central purchasing unit and outlets) under disruption risk. The final demand is deterministic. Suppliers are located in different geographic areas, and supplies are subject to a positive probability of disruption. Different capacity and failure probabilities for each supplier are considered. Our analysis focuses on the insurance versus profitability trade-off faced by a supply manager who buys from suppliers for the outlets. Instead of determining optimal decisions given an objective function and the risk sensitivity of the decision-maker, we use a mixed integer linear programming approach to provide decision-making support that shows a supply manager the ‘elasticity of (expected) losses versus (expected) profits’. Under this model, and depending on the profit-and-loss targets, a supply manager of known risk sensitivity (i.e. risk aversion and loss aversion) can make better decisions when choosing suppliers. Moreover, taking into account, the impact of the share of fixed costs that must be covered by the operation, we consider the net values of expected profit and loss. We discuss the potential influence of the level of the firm’s fixed costs on the supply strategy. In particular, we show how the minimum value of the gross margin needed for the strategy’s profitability affects that strategy. A numerical application is conducted to illustrate the contribution of our decision-making support mechanism, and several managerial insights are obtained.     

Critical attributes of transdermal drug delivery system (TDDS) – a generic product development review

Bioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two products. These current regulatory procedures demand a complete characterization of the generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of products and also outlines their valuable applications in generic product success. Understanding these critical in vitro parameters can probably help to decode the complex bioequivalence outcomes, directing the generic companies to optimize the formulation design in reduced time intervals. It is difficult to summarize a common platform which covers all possible transdermal products; hence few case studies based on this approach has been presented in this review.     

In vitro evaluation of folic acid modified carboxymethyl chitosan nanoparticles loaded with doxorubicin for targeted delivery

The development of smart targeted nanoparticle that can deliver drugs to direct cancer cells, introduces better efficacy and lower toxicity for treatment. We report the development and characterizations of pH-sensitive carboxymethyl chitosan modified folic acid nanoparticles and manifest their feasibility as an effective targeted drug delivery vehicle. The nanoparticles have been synthesized from carboxymethyl chitosan with covalently bonded bifunctional 2,2′-(ethylenedioxy)-bis-(ethylamine) (EDBE) through the conjugation with folic acid. The conjugation has been analyzed by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. The resultant nanoparticles with an average size less then 200 nm measured by dynamic light scattering and transmission electron microscopy. Confocal microscopy and flow cytometric analysis have revealed that folate-mediated targeting significantly enhances the cellular uptake of the nanoparticle and thus facilitates apoptosis of cancer cells (HeLa, B16F1). For the application of the nanoparticles as a drug carrier, Doxorubicin a potent anticancer drug has been loaded into the nanoparticles, with the drug loading amount and the drug release pattern observed.