In vitro-in vivo correlation and bioavailability studies of captopril from novel controlled release donut shaped tablet

A controlled release formulation of captopril which was coated and fabricated into a donut shaped tablet formulation, was investigated in rabbit for pharmacokinetic and in vitro-in vivo correlation studies. Coated donut shaped tablets were prepared and in vitro release was studied in simulated gastric fluid at three different RPMs. New Zealand albino male rabbits have been used as animal model for in vivo study. A sensitive and simple HPLC method was developed for the determination of captopril content in rabbit plasma. In vitro release studies showed that release patterns followed zero order for around 4 h. Single oral administration of coated donut shaped tablets in rabbit illustrated retained availability of captopril to the injected drug. Captopril content could pursue the same release pattern over the same time course in in vivo study. The in vivo-in vitro correlation coefficients obtained from point-to-point analysis were greater than 99% between concentrations at certain time points obtained from release study in simulated gastric fluid at different RPMs and HPLC analysis of rabbit's plasma. From the in vitro-in vivo correlation prediction it was evident that the coated donut shaped tablet is a good device for controlled delivery of captopril.     

New functional degradable and bio-compatible nanoparticles based on poly(malic acid) derivatives for site-specific anti-cancer drug delivery

Design of an efficient site-specific drug delivery system based on degradable functional polymers still remains challenging. In this work, we synthesized and characterized three degradable functional polyesters belonging to the poly(malic acid) family: the poly(benzyl malate) (PMLABe), the poly(ethylene glycol)-b-poly(benzyl malate) (PEG₄₂-b-PMLABe), the biotin-poly(ethylene glycol)-b-poly(benzyl malate) (Biot-PEG₆₂-PMLABe). Starting from these building blocks, we were able to prepare the corresponding well-defined degradable functional nanoparticles whose toxicity was evaluated in vitro on normal and cancer cell lines. Results have evidenced that the prepared nanoparticles did not show any significant cytotoxicity even at high concentrations. A model anti-cancer drug (doxorubicin, Dox) or a fluorescent probe (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine, DiD oil) has been encapsulated into PMLABe, PEG₄₂-PMLABe or Biot-PEG₆₂-PMLABe based nanoparticles in order to evaluate, respectively, the in vitro cytotoxicity of Dox-loaded nanoparticles on normal and cancer cell lines and the ligand (biotin) effect on cellular uptake in vitro using mmt 060562 cell line. Dox-loaded PMLABe, PEG₄₂-PMLABe or Biot-PEG₆₂-PMLABe nanoparticles showed an in vitro cytotoxicity similar to that of free Dox. Moreover, the DiD oil loaded Biot-PEG₆₂-PMLABe based nanoparticles showed a better in vitro cellular uptake than ligand-free DiD oil loaded nanoparticles. Both results evidence the great potential of such degradable functional poly(malic acid) derivatives for the design of highly efficient site-specific anti-cancer nanovectors.     

Nanostructured porous silicon microparticles enable sustained peptide (Melanotan II) delivery

Peptide molecules can improve the treatment of a number of pathological conditions, but due to their physicochemical properties, their delivery is very challenging. The study aim was to determine whether nanostructured porous silicon could sustain the release and prolong the duration of action of a model peptide Melanotan II (MTII). Thermally hydrocarbonized nanoporous silicon (THCPSi) microparticles (38-53 μm) were loaded with MTII. The pore diameter, volume, specific surface area and loading degree of the microparticles were analyzed, and the peptide release was evaluated in vitro. The effects of MTII on heart rate and water consumption were investigated in vivo after subcutaneous administration of the MTII loaded microparticles. A peptide loading degree of 15% w/w was obtained. In vitro studies (PBS, pH 7.4, 37 °C) indicated sustained release of MTII from the THCPSi microparticles. In vivo, MTII loaded THCPSi induced an increase in the heart rate 2 h later than MTII solution, and the effect lasted 1 h longer. In addition, MTII loaded THCPSi changed the water consumption after 150 min, when the immediate effect of MTII solution was already diminished. The present study demonstrates that MTII loading into nanosized PSi pore structure enables sustained delivery of an active peptide.     

Dexamethasone-containing biodegradable superparamagnetic microparticles for intra-articular administration: Physicochemical and magnetic properties, in vitro and in vivo drug release

Compared with traditional drug solutions or suspensions, polymeric microparticles represent a valuable means to achieve controlled and prolonged drug delivery into joints, but still suffer from the drawback of limited retention duration in the articular cavity. In this study, our aim was to prepare and characterize magnetic biodegradable microparticles containing dexamethasone acetate (DXM) for intra-articular administration. The superparamagnetic properties, which result from the encapsulation of superparamagnetic iron oxide nanoparticles (SPIONs), allow for microparticle retention with an external magnetic field, thus possibly reducing their clearance from the joint. Two molecular weights of poly(lactic-co-glycolic acid) (PLGA) were used, 12 and 19 kDa. The prepared batches were similar in size (around 10 μm), inner morphology, surface morphology, charge (neutral) and superparamagnetic behaviour. The SPION distribution in the microparticles assessed by TEM indicates a homogeneous distribution and the absence of aggregation, an important factor for preserving superparamagnetic properties. DXM release profiles were shown to be quite similar in vitro (ca. 6 days) and in vivo, using a mouse dorsal air pouch model (ca. 5 days).     

A novel gastroretentive porous microparticle for anti-Helicobacter pylori therapy: Preparation, in vitro and in vivo evaluation

Gastroretentive drug delivery system is a promising option for the treatment of Helicobacter pylori infection, which can prolong gastric residence time and supply high drug concentration in the stomach. In the present study, a low density system of metronidazole-loaded porous Eudragit^® RS microparticle with high drug loading capacity (>25%) was fabricated via electrospray method. The porous structure and size distribution of microparticles were affected by polymer concentration and flow rate of solution. FTIR and XRD analyses indicated that drug has been entrapped into the porous microparticles. In addition, sustained release profiles and slight cytotoxicity in vitro were detected. Gamma scintigraphy study in vivo demonstrated that ¹³¹I-labeled microparticles retained in stomach for over 8 h, and about 65.50% radioactive counts were finally detected in the region of interest. The biodistribution study confirmed that hotspot of radioactivity was remaining in the stomach. Furthermore, metronidazole-loaded porous microparticles can eradicate H. pylori completely with lower dose and administration frequency of antibiotic compared with pure drug, which were also more helpful for the healing of mucosal damages. These results suggest that prepared porous microparticle has the potential to provide better treatment for H. pylori infection.     

Diisocyanate mediated polyether modified gelatin drug carrier for controlled release

Gelatin is an extensively studied biopolymer hydrogel drug carrier due to its biocompatibility, biodegradability and non-toxicity of its biodegraded products formed in vivo. But with the pristine gelatin it is difficult to achieve a controlled and desirable drug release characteristics due to its structural and thermal lability and high solubility in aqueous biofluids. Hence it is necessary to modify its solubility and structural stability in biofluids to achieve controlled release features with improved drug efficacy and broader carrier applications. In the present explorations an effort is made in this direction by cross linking gelatin to different extents using hitherto not studied isocyanate terminated poly(ether) as a macrocrosslinker prepared from poly(ethylene glycol) and isophorone diisocyanate in dimethyl sulfoxide. The crosslinked samples were analyzed for structure by Fourier transform-infrared spectroscopy, thermal behavior through thermogravimetric analysis and differential scanning calorimetry. The cross linked gelatins were biodegradable, insoluble and swellable in biofluids. They were evaluated as a carrier for in vitro drug delivery taking theophylline as a model drug used in asthma therapy. The crosslinking of gelatin decreased the drug release rate by 10–20% depending upon the extent of crosslinking. The modeled drug release characteristics revealed an anomalous transport mechanism. The release rates for ampicillin sodium, 5-fluorouracil and theophylline drugs in a typical crosslinked gelatin carrier were found to depend on the solubility and hydrophobicity of the drugs, and the pH of the fluid. The observed results indicated that this material can prove its mettle as a viable carrier matrix in drug delivery applications.     

<Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">In Vivo</Emphasis> Drug Release from a Novel <Emphasis Type="BoldItalic">In Situ</Emphasis> Forming Drug Delivery System

Purpose The objective of this work was to investigate the influence of various preparation and formulation parameters on the in vitro and in vivo release of bupivacaine hydrochloride from an injectable in situ forming microparticle system (ISM). Methods The in vitro drug release of ISM was investigated as a function of various formulation and process parameters and was compared to the drug release from in situ forming implants and conventional microparticles. In vivo studies were carried out in male Sprague–Dawley rats. Results Upon contact with an aqueous medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems was reduced with decreasing polymer phase/external oil phase ratio. An advantage of the ISM system compared to in situ implant systems was the significantly reduced burst effect, resulting in drug release profiles comparable to microparticles prepared by conventional methods. The in vivo drug release studies were in good agreement with the in vitro drug release. With the ISM system, the analgesic effect of the bupivacaine hydrochloride was prolonged when compared to the injection of a drug solution or drug-polymer solution. Conclusions ISM are an attractive alternative for parenteral drug delivery systems.     

Correlation between in vitro and in vivo erosion behaviour of erodible tablets using gamma scintigraphy

In vitro and in vivo erosion behaviour of erodible tablets consisting of glyceryl behenate and low-substituted hydroxypropylcellulose manufactured using three different methods: direct compression (DC), melt granulation (MG) and direct solidification (DS) was investigated. In vitro erosion behaviour was studied using gravimetric and scintigraphic methods. For scintigraphic investigations, the radiolabel was adsorbed onto activated charcoal and incorporated into tablets at a concentration that did not affect the erosion profile. A clinical study was carried out in six healthy volunteers using gamma scintigraphy. Tablet erosion was affected by the preparation method and was found to decrease in the order of preparation method, DC > MG > DS tablets. The mean in vivo onset time for all tablets (DC: 6.7 ± 3.8 min, MG: 18.3 ± 8.1 min, DS: 67 ± 18.9 min) did not differ significantly from in vitro onset time (DC: 5.3 ± 1 min, MG: 16.8 ± 3.9 min, DS: 61.8 ± 4.7 min). The mean in vivo completion times were found to be 36.6 ± 9.7 (DC tablets), 70 ± 18.3 min (MG tablets) and 192.5 ± 39.9 min (DS tablets). Among the three different erodible tablets, MG tablets showed the highest correlation between in vitro and in vivo mean erosion profile and suggested a potential platform to deliver controlled release of water-insoluble compounds.     

Targeted delivery of a poorly water-soluble compound to hair follicles using polymeric nanoparticle suspensions

This study explored the utility of topically applied polymeric nanoparticle suspensions to target delivery of poorly water-soluble drugs to hair follicles. Several formulations of amorphous drug/polymer nanoparticles were prepared from ethyl cellulose and UK-157,147 (systematic name (3S,4R)-[6-(3-hydroxyphenyl)sulfonyl]-2,2,3-trimethyl-4-(2-methyl-3-oxo-2,3-dihydropyridazin-6-yloxy)-3-chromanol), a potassium channel opener, using sodium glycocholate (NaGC) as a surface stabilizer. Nanoparticle suspensions were evaluated to determine if targeted drug delivery to sebaceous glands and hair follicles could be achieved. In in vitro testing with rabbit ear tissue, delivery of UK-157,147 to the follicles was demonstrated with limited distribution to the surrounding dermis. Delivery to hair follicles was also demonstrated in vivo, based on stimulation of hair growth in tests of 100-nm nanoparticles with a C3H mouse model. The nanoparticles were well-tolerated, with no visible skin irritation. In vivo tests of smaller nanoparticles with a hamster ear model also indicated targeted delivery to sebaceous glands. The nanoparticles released drug rapidly in in vitro nonsink dissolution tests and were stable in suspension for 3 months.The present results show selective drug delivery to the follicle by follicular transport of nanoparticles and rapid release of a poorly water-soluble drug. Thus, nanoparticles represent a promising approach for targeted topical delivery of low-solubility compounds to hair follicles.     

Preparation of sustained release microparticles with improved initial release property

The objective of this study was to investigate the potential of various formulation strategies to achieve sustained release of the peptide, from injectable poly(D,L-lactide-co-glycolide) (PLGA) and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) microparticles. The microparticles were prepared by a solvent evaporation method. Peptide loaded PLGA microparticles exhibited a pronounced initial burst release (22.3% in 1 day) and lag phase in phosphate buffer of pH 7.0. In contrast, blending of 5.0% TPGS (8.6% release in 1 day) or 10.0% TPGS (5.5% release in 1 day) in PLGA microparticles reduced initial burst release and the lag-phase time. Incorporation of TPGS in PLGA microparticles further increased drug release, attributable to improved drug encapsulation, increased particle size, and exempt of pores. PLGA+ 10.0% TPGS composite microparticles exhibited the most desirable drug release among all the formulations tested, and demonstrated triphasic release after minimal initial burst.     

Development and validation of a rapid reversed-phase HPLC method for the determination of the non-nucleoside reverse transcriptase inhibitor dapivirine from polymeric nanoparticles

The objective of this work was to develop and validate a rapid reversed-phase (RP) high-performance liquid chromatography (HPLC) method for the in vitro pharmaceutical characterization of dapivirine-loaded polymeric nanoparticles. Chromatographic runs were performed on a RP C18 column with a mobile phase comprising acetonitrile–0.5% (w/v) triethanolamine solution in isocratic mode (80:20, v/v) at a flow rate of 1 ml/min. Dapivirine was detected at a wavelength of 290 nm. The method was shown to be specific, linear in the range of 1–50 μg/ml (R² = 0.9998), precise at the intra-day and inter-day levels as reflected by the relative standard deviation values (less than 0.85%), accurate (recovery rate of 100.17 ± 0.35%), and robust to changes in the mobile phase and column brand. The detection and quantitation limits were 0.08 and 0.24 μg/ml, respectively. The method was successfully used to determine the loading capacity and association efficiency of dapivirine in poly(lactic-co-glycolic acid)-based nanoparticles and its in vitro release.     

A novel strategy to design sustained-release poorly water-soluble drug mesoporous silica microparticles based on supercritical fluid technique

Background

The organic solvent solution immersion method was often used to achieve the loading of the drugs into mesoporous silica, but the drugs that have loaded into the pores of the mesoporous silica would inevitable migrate from the inside to the external surface or near the outside surface during the process of drying. Hence, it often leads to the pores of mesoporous materials not be fully utilized, and results in a low drug loading efficiency and a fast releasing rate.

Objective

The purpose of this study was to develop a novel drug loading strategy to avoid soluble component migration during the process of drying, then, to prepare poorly water-soluble drug mesoporous silica microparticles with higher drug loading efficiency and longer sustained-release time.

Method

Ibuprofen was used as model drug. The microparticles were prepared by a novel method based on mesoporous silica and supercritical fluid (SCF) technique. The drug-loaded mesoporous silica microparticles prepared by SCF technique were analyzed by thermogravimetric analysis (TGA), N₂ adsorption/desorption, scanning electron microscopy (SEM), powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). In vitro releasing study was used to evaluate the sustained-release effect of the drug-loaded microparticles.

Results

By virtue of the high diffusibility and the high dissolving capacity of the supercritical carbon dioxide (SCF-CO₂), the poorly water-soluble drugs, ibuprofen, entered the pores of the mesoporous silica. The amount and the depth of ibuprofen entered the pores of the mesoporous silica by SCF technique were both larger than those by the solution immersion method. It was found that ibuprofen loaded into the mesoporous silica by SCF technique was amorphous and the largest amount of the ibuprofen loaded into the mesoporous silica by SCF technique could reach 386 mg/g (w/w, ibuprofen/SiO₂), it was more than that by the solution immersion method. In vitro releasing study showed that the sustained-release effect of ibuprofen in the samples prepared by SCF technique was 50% in 15 min and 90% in 60 min. It was longer than that prepared by the solution immersion method.

Conclusion

Present study showed that sustained-release poorly water-soluble drug mesoporous silica microparticle based on SCF technique has twofold advantages. One is the larger drug loading amount in internal pores of the mesoporous silica, the other is the longer drug releasing time.     

Encapsulation of poorly soluble basic drugs into enteric microparticles: a novel approach to enhance their oral bioavailability

Poorly water soluble basic drugs are very sensitive to pH changes and following dissolution in the acidic stomach environment tend to precipitate upon gastric emptying, which leads to compromised or erratic oral bioavailability. In this work, we show that the oral bioavailability of a model poorly soluble basic drug (cinnarizine) can be improved by drug encapsulation within highly pH-responsive microparticles (Eudragit L). The latter was prepared by emulsion solvent evaporation which yielded discrete spherical microparticles (diameter of 56.4 ± 6.8 μm and a span of 1.2 ± 0.3). These Eudragit L (dissolution threshold pH 6.0) microparticles are expected to dissolve and release their drug load at intestinal conditions. Thus, the enteric microparticles inhibited the in vitro release of drug under gastric conditions, despite high cinnarizine solubility in the acidic medium. At intestinal conditions, the particles dissolved rapidly and released the drug which precipitated out in the dissolution vessel. In contrast, cinnarizine powder showed rapid drug dissolution at low pH, followed by precipitation upon pH change. Oral dosing in rats resulted in a greater than double bioavailability of Eudragit L microparticles compared to the drug powder suspension, although C_max and T_max were similar. The higher bioavailability with microparticles contradicts the in vitro results. Such an example highlights that although in vitro results are an indispensable tool for formulation development, an early in vivo assessment of formulation behaviour can provide better prediction for oral bioavailability.     

Physicochemical aspects of doxorubicin-loaded pH-sensitive polymeric micelle formulations from a mixture of poly(l-histidine)-b-poly(l-lactide)-b-poly(ethylene glycol)

In this study, doxorubicin (DOX) was physically incorporated into pH-sensitive micelles made from a mixture of poly(l-histidine)-b-poly(ethylene glycol)/poly(l-lactide)-b-poly(ethylene glycol) (75/25, wt.%). The DOX-loaded mixed micelles were formulated using dialysis methods and optimal DOX incorporation was achieved at a drug/polymer feed ratio of 0.2 (wt./wt.) when a proper amount of aqueous phase (0.2, v./v.) was added into the common solvent (DMSO) solution, followed by dialysis at 4 °C. Based on the results obtained from dynamic light scattering, UV-Vis absorption, and fluorescence experiments, it was demonstrated that the encapsulated drugs were mainly located inside the hydrophobic micelle cores, well protected and inaccessible to the exterior molecules. Under in vitro conditions, although the microstructure of the micelles was altered below pH 8.0 by the encapsulated drugs, the drug-loaded micelles still exhibited a desirable ability to control the drug release in response to tumor extracellular pH.     

In vitro and ex vivo angiogenic effects of roxarsone on rat endothelial cells

Roxarsone, a feed additive, is being used worldwide to promote animal growth. However, the potential effect of roxarsone on angiogenesis has not been extensively characterized. We examined the ability of roxarsone to promote angiogenesis of rat endothelial cells in vitro and from rat aorta rings ex vivo. Endothelial cells from rats were exposed to 0.01–10.00 μM roxarsone, 5 ng/mL vascular endothelial growth factor (VEGF) as a positive control or phosphate buffer saline (PBS) as a negative control. Cell proliferation was measured by MTT assay, and the content of VEGF in supernatants was measured by enzyme-linked immunosorbent assay and Western blotting. A Matrigel-induced tube formation assay was used to evaluate the effects of roxarsone on endothelial cells. Additionally, the total number and length of microvessels sprouted from rat aortic rings were measured for ex vivo investigation of angiogenesis. Results showed that the cell viability and total number and length of capillary-like tube formations after roxarsone treatment was significantly higher than that of negative (P < 0.05), with a maximum effect at 1.00 μM exposure. Furthermore, the number of microvessels sprouted from aortic rings treated for 4 h with 0.1–10.0 μM roxarsone was significantly higher than that of PBS treatment, with a peak value of 1.0 μM. These results further demonstrate the potential of roxarsone to promote angiogenesis in vitro and ex vivo.     

Antioxidant activity and protective effect of Turnera ulmifolia Linn. var. elegans against carbon tetrachloride-induced oxidative damage in rats

The present study aimed to determine whether the leaves of Turnera ulmifolia Linn. var. elegans extract exert significant antioxidant activity. The antioxidant activity of its hydroethanolic extract (HEETU) was evaluated by assessing (a) its radical scavenging ability in vitro, and (b) its in vivo effect on lipid peroxidation and antioxidant enzyme activities. The in vitro antioxidant assay (DPPH) clearly supported HEETU free radical scavenging potential. Moreover, glutathione content and antioxidant enzyme activities (glutathione peroxidase, superoxide dismutase and catalase) were significantly enhanced in CCl₄-treated rats due to oral HEETU-treatment (500 mg/kg b.w.) over 7 and 21 days. In addition, an improvement was observed in lipid peroxidation and serum biochemical parameters (aspartate aminotransferase and alanine aminotransferase), indicating a protective effect against CCl₄-induced liver injuries, confirmed by histopathological studies. The HEETU effect was comparable to the standard drug Legalon® (50 mg/kg b.w.) under the same experimental condition. Quantitative analysis of the HPLC extract revealed the presence of flavonoids, wich mediate the effects of antioxidant and oxidative stress. In conclusion, extract components exhibit antioxidant and hepatoprotective activities in vitro and in vivo.     

Novel,dynamic on-line analytical separation system for dissolution of drugs from poly(lactic acid) nanoparticles

A novel method for investigating drug release in a dynamic manner from nanoparticles including, but not limited to, biodegradable poly(lactic acid) (PLA) is reported. The PLA nanoparticles were prepared by the nanoprecipitation method. Two poorly soluble drugs, beclomethasone dipropionate (BDP) and indomethacin, were encapsulated into PLA nanoparticles, and their dissolution from the nanoparticles were followed in a dynamic way. The on-line method comprised a short column (vessel) packed with the PLA nanoparticles, on-line connected to an analytical liquid chromatographic column via a multiport switching valve equipped with two loops. The system allowed monitoring of the drug release profiles in real time, and the conditions for the drug release could be precisely controlled and easily changed. The effects of solvent composition and temperature on the rate of dissolution of the drugs from the PLA nanoparticles were investigated. The system proved to be linear for the drugs tested over the concentration range 10–3000 ng (n = 6, R² = 0.999 and 0.997 for indomethacin and beclomethasone, respectively) and repeatable (RSD of peak areas <0.5%). The recoveries of the dissolution study were quantitative (120 and 103% for indomethacin and beclomethasone, respectively).     

VEGF-controlled release within a bone defect from alginate/chitosan/PLA-H scaffolds

VEGF and its receptors constitute the key signaling system for angiogenic activity in tissue formation, but a direct implication of the growth factor in the recruitment, survival and activity of bone forming cells has also emerged. For this reason, we developed a composite (alginate/chitosan/PLA-H) system that controls the release kinetics of incorporated VEGF to enhance neovascularization in bone healing. VEGF release kinetics and tissue distribution were determined using iodinated (¹²⁵I) growth factor. VEGF was firstly encapsulated in alginate microspheres. To reduce the high in vitro burst release, the microspheres were included in scaffolds. Matrices were prepared with alginate (A-1, A-2), chitosan (CH-1, CH-2) or by coating the CH-1 matrix with a PLA-H (30 kDa) film (CH-1-PLA), the latter one optimally reducing the in vitro and in vivo burst effect. The VEGF in vitro release profile from CH-1-PLA was characterized by a 13% release within the first 24 h followed by a constant release rate throughout 5 weeks. For VEGF released from composite scaffolds in vitro, bioactivity was maintained above 90% of the expected value. Despite the fact that the in vivo release rate was slightly faster, a good in vitro–in vivo correlation was found. The VEGF released from CH-1 and CH-1-PLA matrices implanted into the femurs of rats remained located around the implantation site with a negligible systemic exposure. These scaffolds provided a bone local GF concentration above 10 ng/g during 2 and 5 weeks, respectively, in accordance to the in vivo release kinetics. Our data show that the incorporation of VEGF into the present scaffolds allows for a controlled release rate and localization of the GF within the bone defect.     

Surfactant-free redispersible nanoparticles in fast-dissolving composite microcarriers for dry-powder inhalation

Spray-drying was investigated for the stabilization of surfactant-free nanoparticles as carriers for dry-powder inhalers. The microparticles rapidly dissolve after inhalation yielding dispersed nanoparticles.Nanoparticles were prepared by a solvent displacement technique avoiding any surfactants. Microcarriers were prepared by spray-drying nanoparticle suspensions with lactose, mannitol or α-cyclodextrin as stabilizers. Nanoparticle size and ζ-potential before and after spray-drying were analyzed with photon correlation spectroscopy and laser Doppler anemometry, respectively. Cell uptake into macrophages was studied using U 937 cells by confocal microscopy.Stabilization of nanoparticle suspensions by spray-drying with α-cyclodextrin yielded redispersible particles smaller than 200 nm. α-Cyclodextrin was a more efficient stabilizer than commonly used excipients. Microparticles with a mass median aerodynamic diameter of 4.3 μm showed properties suitable for dry-powder inhalation. The cell culture experiments with redispersed nanoparticles seem to suggest less interaction and uptake with macrophages compared to polymeric microparticles.In conclusion, nanoparticles can easily be transferred to dry-powders suitable for inhalation by spray-drying. This allows the pulmonary application of nanoparticles in high concentrations.     

Preparation and characterization of D,L-PLA loaded 17-β-Estradiol valerate by emulsion/evaporation methods

PLA microparticles containing 17-β-estradiol valerate were prepared by an emulsion/evaporation method in order to sustain drug release. This system was characterized concerning particle size, particle morphology and the influence of formulation and processing parameters on drug encapsulation and in vitro drug release. The biodegradation of the microparticles was observed by tissue histological analysis. Scanning electron microscopy and particle size analysis showed that the microparticles were spherical, presenting non-aggregated homogeneous surface and had diameters in the range of 718–880 nm (inert micro-particles) and 3–4 µm (drug loaded microparticles). The encapsulation efficiency was ～80%. Hormone released from microparticles was sustained. An in vivo degradation experiment confirmed that microparticles are biodegradable. The preparation method was shown to be suitable, since the morphological characteristics and efficiency yield were satisfactory. Thus, the method of developed microparticles seems to be a promising system for sustained release of 17-β-estradiol.