International Journal of Pharmaceutics (v.482, #1-2)
EDITORIAL BOARD (iii).
Editorial to European workshop on particulate systems in nanomedicine (2014) by René van Nostrum; Gert Storm (1).
Monoclonal antibody-targeted PEGylated liposome-ICG encapsulating doxorubicin as a potential theranostic agent by Neus Lozano; Zahraa S. Al-Ahmady; Nicolas S. Beziere; Vasilis Ntziachristos; Kostas Kostarelos (2-10).
Display OmittedIndocyanine green (ICG) is an FDA-approved, strongly photo-absorbent/fluorescent probe that has been incorporated into a clinically-relevant PEGylated liposome as a flexible optoacoustic contrast agent platform. This study describes the engineering of targeted PEGylated liposome-ICG using the anti-MUC-1 “humanized” monoclonal antibody (MoAb) hCTM01 as a tumour-specific theranostic system. We aimed to visualise non-invasively the tumour accumulation of these MoAb-targeted liposomes over time in tumour-bearing mice using multispectral optoacoustic tomography (MSOT). Preferential accumulation of targeted PEGylated liposome-ICG was studied after intravenous administration in comparison to non-targeted PEGylated liposome-ICG using both fast growing (4T1) and slow growing (HT-29) MUC-1 positive tumour models. Monitoring liposomal ICG in the tumour showed that both targeted and non-targeted liposome-ICG formulations preferentially accumulated into the tumour models studied. Rapid accumulation was observed for targeted liposomes at early time points mainly in the periphery of the tumour volume suggesting binding to available MUC-1 receptors. In contrast, non-targeted PEGylated liposomes showed accumulation at the centre of the tumour at later time points. In an attempt to take this a step further, we successfully encapsulated the anticancer drug, doxorubicin (DOX) into both targeted and non-targeted PEGylated liposome-ICG. The engineering of DOX-loaded targeted ICG liposome systems present a novel platform for combined tumour-specific therapy and diagnosis. This can open new possibilities in the design of advanced image-guided cancer therapeutics.
Keywords: Cancer nanotechnology; Optical imaging; Targeting; Photoacoustics; Nanomedicine;
CapsMorph® technology for oral delivery – theory, preparation and characterization by Qionghua Wei; Cornelia M. Keck; Rainer H. Müller (11-20).
Display OmittedThe CapsMorph® technology prepares amorphous drugs for oral delivery by encapsulating them into porous materials. Hesperidin as model compound was loaded onto AEROPERL® 300 Pharma using the wetness impregnation method. Hesperidin was dissolved in dimethyl sulfoxide (DMSO) and alternatively in DMSO with addition of Tween 80. The drug solutions were added dropwise to the porous material and subsequently DMSO was evaporated. The AEROPERL® 300 Pharma could be loaded with about 30% hesperidin in the amorphous form. Amorphous state was verified by X-ray diffraction and differential scanning calorimetry. The CapsMorph® formulation was compared regarding properties determining oral bioavailability, i.e., kinetic saturation solubility and dissolution rate to raw drug powder and hesperidin nanocrystals. The saturation solubility of CapsMorph® without Tween 80 was 654 μg/ml, which is 36-fold higher than the raw drug powder (18 μg/ml) and about 20 times higher than nanocrystals (30 μg/ml). In vitro release was faster (100% in 10 min at pH 6.8) compared to dissolution of nanocrystals with about 15%. Addition of Tween 80 to CapsMorph® lowered the solubility (168 μg/ml) and slowed down the release, but provided longer times of supersaturation without precipitation of drug. Based on these data, it appears that drug loaded porous materials provide better formulations compared to nanocrystals for poorly soluble drugs.
Keywords: CapsMorph®; AEROPERL® 300 Pharma; Hesperidin; Impregnation; Amorphous; Saturation solubility; Oral bioavailability; Poorly soluble drugs;
Novel oral phosphate binder with nanocrystalline maghemite-phosphate binding capacity and pH effect by T.M.-H. Nguyen; R.H. Müller; M. Taupitz; J. Schnorr; B. Hamm; S. Wagner (21-26).
Display OmittedHyperphosphatemia is one of the main risk factors contributing to morbidity and mortality in patients with end stage renal disease. The demand for a new phosphate binder is continuously increasing since the number of patients suffering under hyperphosphatemia is growing. However, side effects and high pill burden of currently available phosphate binders are the main reasons for low compliance and uncontrolled serum phosphate levels. Therefore, the aim of this study was to develop a novel phosphate binder with a high phosphate binding capacity over the entire gastrointestinal (GI) pH range. This novel phosphate binder C-PAM-10 is based on d-mannose coated nanocrystalline maghemite and belongs to the new class of phosphate binders, called the “iron based agents”. It was possible to obtain a phosphate binding product that showed very high phosphate binding capacities with the characteristic of being pH independent at relevant pH ranges. The simulation of a GI passage ranging from pH 1.2 to pH 7.5 showed a 2.5 times higher phosphate binding capacity compared to the commonly used phosphate binder sevelamer carbonate. The simulation of a pH sensitive coating that releases the iron based phosphate binder at pH values ≥4.5 still showed a very high phosphate binding capacity combined with very low iron release which might decrease iron related side effects in vivo. Therefore, C-PAM-10 and its variations may be very promising candidates as a superior phosphate binder.
Keywords: Phosphate binder; Nanocrystals; Maghemite; pH effect; Iron release;
Flavonoid nanocrystals produced by ARTcrystal®-technology by Patrik Scholz; Cornelia M. Keck (27-37).
Display OmittedARTcrystal®-technology is a novel technique for a more efficient production of nanocrystals. It consists of a high speed stirring (HSS) step as pre-milling and subsequent high pressure homogenization (HPH) at reduced pressure and cycle numbers. In this study, three antioxidants, rutin, hesperidin and apigenin, were processed by ARTcrystal®-technology, the results were compared to sizes obtained for the production of nanocrystals produced by classical HPH. By using the ARTcrystal®-process, all three substances could be transformed into nanosuspensions with mean sizes and PdIs of 431 nm/0.27, 717 nm/0.21 and 262 nm/0.31, respectively. Depending on the properties of the raw material the ARTcrystal®-technology revealed similar or even better results than classical HPH. Further optimization of the setup of the HSS process might lead to an optimized process with higher efficacy than classical HPH.
Keywords: ARTcrystal; Nanocrystal; Rutin; Hesperidin; Apigenin;
Gemcitabine-based therapy for pancreatic cancer using the squalenoyl nucleoside monophosphate nanoassemblies by Andrei Maksimenko; Joachim Caron; Julie Mougin; Didier Desmaële; Patrick Couvreur (38-46).
Display OmittedGemcitabine is currently the most effective agent against advanced pancreatic cancer. However, the major therapeutic hurdles using gemcitabine include rapid inactivation by blood deaminases and fast development of cell chemoresistance, induced by down-regulation of deoxycytidine kinase or nucleoside transporters. To overcome the above drawbacks we designed recently a novel nanomedicine strategy based on squalenoyl prodrug of 5′-monophosphate gemcitabine (SQdFdC-MP). This amphiphilic conjugate self-organized in water into unilamellar vesicles with a mean diameter of 100 nm. In this study the antitumor efficacy of SQdFdC-MP nanoassemblies (NAs) on chemoresistant and chemosensitive pancreatic adenocarcinoma models have been investigated. Cell viability assays showed that SQdFdC-MP NAs displayed higher antiproliferative and cytotoxic effects, particularly in chemoresistant pancreatic tumor cells. In in vivo studies, SQdFdC-MP NAs decreased significantly the growth (∼70%) of human MiaPaCa2 xenografts, also preventing tumor cell invasion, whereas native dFdC did not display any anticancer activity when tumor growth inhibition was only 35% with SQdFdC NAs. These results correlated with a reduction of Ki-67 antigen and the induction of apoptosis mediated by caspase-3 activation in tumor cells. These findings demonstrated the feasibility of utilizing SQdFdC-MP NAs to make tumor cells more sensitive to gemcitabine and thus providing an efficient new therapeutic alternative for pancreatic adenocarcinoma.
Keywords: Gemcitabine; Squalenoyl prodrug; Pancreatic cancer; Deoxycytidine kinase; Nanoassemblies;
Holmium–lipiodol–alginate microspheres for fluoroscopy-guided embolotherapy and multimodality imaging by Chris Oerlemans; Peter R. Seevinck; Maarten L. Smits; Wim E. Hennink; Chris J.G. Bakker; Maurice A.A.J. van den Bosch; J. Frank W. Nijsen (47-53).
Display OmittedEmbolotherapy is a minimally invasive transcatheter technique aiming at reduction or complete obstruction of the blood flow by infusion of micro-sized particles in order to induce tumor regression. A major drawback of the current commercially available and clinically used microspheres is that they cannot be detected in vivo with medical imaging techniques, impeding intra- and post-procedural feedback. It can be expected that real-time monitoring of microsphere infusion and post-procedural imaging will result in better predictability and higher efficacy of the treatment. In this study, a novel microsphere formulation has been developed that can be visualized with fluoroscopy, X-ray computed tomography (CT) and magnetic resonance imaging (MRI). The microspheres were prepared with the JetCutter technique and consist of alginate (matrix-forming polymer), holmium (cross-linking and MRI contrast agent), lipiodol (radiopaque contrast agent) and Pluronic F-68 (surfactant). The mean size (±SEM) of the hydrated holmium–lipiodol–alginate microspheres (Ho–lip–ams) was 570 ± 12 μm with a holmium content of 0.38 ± 0.01% (w/w). Stability studies showed that the microspheres remained intact during incubation for two weeks in fetal calf serum (FCS) at 37 °C. The inclusion of lipiodol in the microspheres rendered excellent visualization capabilities for fluoroscopy and CT, whereas the holmium ions, which keep the alginate network together, also allow MR imaging. In this study it was shown that single sphere detection was possible by fluoroscopy, CT and MRI. The Ho–lip–ams were visualized in real-time, during infusion in a porcine kidney using fluoroscopy, and post-procedural, the deposition of the microspheres was examined with fluoroscopy, (cone beam rotational) CT and MRI. The different imaging modalities showed similar deposition patterns of the microspheres within the organ. The combination of intra-procedural visualization, multimodality imaging for patient follow-up and the possibility of quantification offers a new and promising method for more safe, efficient and successful embolization treatment.
Keywords: Embolization; Microspheres; Lipiodol; Magnetic resonance imaging (MRI); Computed tomography (CT); X-ray;
Industrial concentrates of dermal hesperidin smartCrystals® – production, characterization & long-term stability by Gregori B. Romero; Run Chen; Cornelia M. Keck; Rainer H. Müller (54-60).
Display OmittedIndustrial concentrates of hesperidin nanocrystals (5.0% nominal concentration) were produced applying the smartCrystal® combination technology of wet bead milling and subsequent high pressure homogenization. Stabilization was performed by Kolliphor® P 188, preservation by Euxyl PE 9010 and glycerol. Physical and chemical stability were monitored over 1.5 years of storage at 4–6 °C. The size of the bulk population stayed unchanged with about 250 nm (photon correlation spectroscopy). Absence of crystal growth by Ostwald ripening and absence of agglomerates were shown by laser diffraction (LD) and light microscopy. The LD diameter 90% was still 0.7 μm after 1.5 years. Despite the large surface of the nanosuspension in contact with the water phase, the chemical content proved also stable, only a reduction by 0.15% from 5.70% to 5.55% content was observed. The nanocrystals kept their crystalline state unchanged as shown by X-ray diffraction. The saturation solubility of the nanosuspension was more than triple compared to the raw drug powder in water. The data show the availability of a stable hesperidin concentrate as intermediate for industry to produce dermal formulations.
Keywords: Nanocrystals; Nanosuspensions; Nanotechnology; Dermal application; Stability; Industrial concentrates;
Establishment and first characterization of a sublingual epithelial and immune cell co-culture model by Gaëlle Vacher; Emmanuelle Sublet; Robert Gurny; Gerrit Borchard (61-67).
Co-cultures of human sublingual epithelial cell line, HO-1-u-1 and dendritic cells derived from peripheral blood monocytes form an immunocompetent in vitro model of the sublingual mucosa.Display OmittedWe describe here the establishment and first characterization of a co-culture model of human epithelial sublingual cells (HO-1-u-1 cell line) and human dendritic cells derived from human peripheral blood monocytes (PBMC). Cell culture conditions for HO-1-u-1 cells were optimized. First characterization of phenotypic features by electron microscopy and fluorescence imaging revealed resemblance to sublingual tissue specimen from healthy donors. Successful co-culturing of epithelial and dendritic cells (DCs) was confirmed by confocal laser scanning microscopy. Stimulation of HO-1-u1 cells alone and the epithelial/DC co-culture by incubation with liposomes, virosomes and influenza virus lead reproducibly to the release of inflammatory cytokine GM-CSF. This co-culture model may be suitable for elucidation of mechanisms involved in the immune response at the sublingual epithelium as well as for the evaluation of novel topical vaccines, potentially replacing cumbersome ex vivo and in vivo methods currently in place.
Keywords: Sublingual epithelium; Co-culture; Dendritic cells; HO-1-u-1 cells; Immunotherapy;
Sunitinib-eluting beads for chemoembolization: Methods for in vitro evaluation of drug release by Katrin Fuchs; Pierre E. Bize; Alban Denys; Gerrit Borchard; Olivier Jordan (68-74).
Display OmittedDrug-eluting microspheres are used for embolization of hypervascular tumors and allow for local controlled drug release. Although the drug release from the microspheres relies on fast ion-exchange, so far only slow-releasing in vitro dissolution methods have been correlated to in vivo data. Three in vitro release methods are assessed in this study for their potential to predict slow in vivo release of sunitinib from chemoembolization spheres to the plasma, and fast local in vivo release obtained in an earlier study in rabbits. Release in an orbital shaker was slow (t 50% = 4.5 h, 84% release) compared to fast release in USP 4 flow-through implant cells (t 50% = 1 h, 100% release). Sunitinib release in saline from microspheres enclosed in dialysis inserts was prolonged and incomplete (t 50% = 9 days, 68% release) due to low drug diffusion through the dialysis membrane. The slow-release profile fitted best to low sunitinib plasma AUC following injection of sunitinib-eluting spheres. Although limited by lack of standardization, release in the orbital shaker fitted best to local in vivo sunitinib concentrations. Drug release in USP flow-through implant cells was too fast to correlate with local concentrations, although this method is preferred to discriminate between different sphere types.
Keywords: In vitro drug release; Sunitinib; Drug-eluting beads; USP dissolution apparatus 4; Chemoembolization; In vitro–in vivo correlation;
Surface coating mediates the toxicity of polymeric nanoparticles towards human-like macrophages by Nadège Grabowski; Hervé Hillaireau; Juliette Vergnaud; Nicolas Tsapis; Marc Pallardy; Saadia Kerdine-Römer; Elias Fattal (75-83).
The purpose of this study was to investigate the toxicity of a series of poly(lactide-co-glycolic) (PLGA) nanoparticles on human-like THP-1 macrophages. Positively-, negatively-charged and neutral nanoparticles (200 nm) were prepared using chitosan (CS), poloxamer 188 (PF68) and poly(vinyl alcohol) (PVA) as stabilizer. Stabilizer-free PLGA nanoparticles were obtained as well.When used at therapeutically relevant concentrations (up to 0.1 mg/mL in vitro), all tested nanoparticles showed no or scarce signs of toxicity, as assessed by cell mitochondrial activity, induction of apoptosis and necrosis, production of intracellular reactive oxygen species (ROS) and secretion of pro-inflammatory cytokines. At high concentrations (above 1 mg/mL), cytotoxicity was found to be induced by the presence of stabilizers, whatever the toxicological pattern of the stabilizer itself. While stabilizer-free PLGA nanoparticles exerted no cytotoxicity, the slightly cytotoxic CS polymer conferred PLGA nanoparticles significant cytotoxicity when used as nanoparticle stabilizer; more surprisingly, the otherwise innocuous PVA and PF68 polymers also conferred a significant cytotoxicity to PLGA nanoparticles.These results unveiled the critical toxicological contribution played by stabilizers used for the formulation of PLGA nanoparticles when used at high concentrations, which may have implications for local toxicities of PLGA-based nanomedicine, and provided additional insight in cytotoxic effects of internalized nanoparticles.
Keywords: PLGA; Stabilizer; Cytotoxicity; Inflammatory response;
Improved insulin loading in poly(lactic-co-glycolic) acid (PLGA) nanoparticles upon self-assembly with lipids by María García-Díaz; Camilla Foged; Hanne Mørck Nielsen (84-91).
Display OmittedPolymeric nanoparticles are widely investigated as drug delivery systems for oral administration. However, the hydrophobic nature of many polymers hampers effective loading of the particles with hydrophilic macromolecules such as insulin. Thus, the aim of this work was to improve the loading of insulin into poly(lactic-co-glycolic) acid (PLGA) nanoparticles by pre-assembly with amphiphilic lipids. Insulin was complexed with soybean phosphatidylcholine or sodium caprate by self-assembly and subsequently loaded into PLGA nanoparticles by using the double emulsion-solvent evaporation technique. The nanoparticles were characterized in terms of size, zeta potential, insulin encapsulation efficiency and loading capacity. Upon pre-assembly with lipids, there was an increased distribution of insulin into the organic phase of the emulsion, eventually resulting in significantly enhanced encapsulation efficiencies (90% as compared to 24% in the absence of lipids). Importantly, the insulin loading capacity was increased up to 20% by using the lipid–insulin complexes. The results further showed that a main fraction of the lipid was incorporated into the nanoparticles and remained associated to the polymer during release studies in buffers, whereas insulin was released in a non-complexed form as a burst of approximately 80% of the loaded insulin. In conclusion, the protein load in PLGA nanoparticles can be significantly increased by employing self-assembled protein-lipid complexes.
Keywords: PLGA nanoparticles; Loading capacity; Oral delivery; Protein–lipid complexes; Self-assembly; Insulin;
Duration of ultrasound-mediated enhanced plasma membrane permeability by Bart Lammertink; Roel Deckers; Gert Storm; Chrit Moonen; Clemens Bos (92-98).
Display OmittedUltrasound (US) induced cavitation can be used to enhance the intracellular delivery of drugs by transiently increasing the cell membrane permeability. The duration of this increased permeability, termed temporal window, has not been fully elucidated. In this study, the temporal window was investigated systematically using an endothelial- and two breast cancer cell lines. Model drug uptake was measured as a function of time after sonication, in the presence of SonoVue™ microbubbles, in HUVEC, MDA-MB-468 and 4T1 cells. In addition, US pressure amplitude was varied in MDA-MB-468 cells to investigate its effect on the temporal window. Cell membrane permeability of HUVEC and MDA-MB-468 cells returned to control level within 1–2 h post-sonication, while 4T1 cells needed over 3 h. US pressure affected the number of cells with increased membrane permeability, as well as the temporal window in MDA-MB-468 cells. This study shows that the duration of increased membrane permeability differed between the cell lines and US pressures used here. However, all were consistently in the order of 1–3 h after sonication.
Keywords: Sonoporation; Ultrasound; Microbubbles; Drug delivery; Membrane permeabilization; Fluorescent model drug;
Biocompatibility of poly(d,l-lactic-co-hydroxymethyl glycolic acid) microspheres after subcutaneous and subcapsular renal injection by F. Kazazi-Hyseni; J. Zandstra; E.R. Popa; R. Goldschmeding; A.A.R. Lathuile; G.J. Veldhuis; C.F. Van Nostrum; W.E. Hennink; R.J. Kok (99-109).
Display OmittedPoly(d,l-lactic-co-hydroxymethyl glycolic acid) (PLHMGA) is a biodegradable copolymer with potential as a novel carrier in polymeric drug delivery systems. In this study, the biocompatibility of PLHMGA microspheres (PLHMGA-ms) was investigated both in vitro in three different cell types (PK-84, HK-2 and PTECs) and in vivo at two implantation sites (by subcutaneous and subcapsular renal injection) in rats. Both monodisperse (narrow size distribution) and polydisperse PLHMGA-ms were prepared with volume weight mean diameter of 34 and 17 μm, respectively. Mono and polydisperse PLHMGA-ms showed good cytocompatibility properties upon 72 h incubation with the cells (100 μg microspheres/600 μL/cell line). A mild foreign body reaction was seen shortly after subcutaneous injection (20 mg per pocket) of both mono and polydisperse PLHMGA-ms with the presence of mainly macrophages, few foreign body giant cells and myofibroblasts. This transient inflammatory reaction diminished within 28 days after injection, the time-point at which the microspheres were degraded. The degradation profile is comparable to the in vitro degradation time of the microspheres (i.e., within 35 days) when incubated at 37 °C in phosphate buffered saline. Subcapsular renal injection of monodisperse PLHMGA-ms (10 mg) in rats was characterized with similar inflammatory patterns compared to the subcutaneous injection. No cortical damage was observed in the injected kidneys. In conclusion, this study demonstrates that PLHMGA-ms are well tolerated after in vivo injection in rats. This makes them a good candidate for controlled delivery systems of low-molecular weight drugs as well as protein biopharmaceuticals.
Keywords: PLHMGA; Cytocompatibility; Biocompatibility; Monodisperse microspheres;
Nanoemulsions produced by rotor–stator high speed stirring by Patrik Scholz; Cornelia M. Keck (110-117).
Display OmittedNanoemulsions were produced by high speed stirring using an ART MICCRA D27 rotor–stator system. Nanoemulsions with a droplet size of 135 nm and a narrow size distribution were obtained. The emulsions are physically stable for at least three months. Optimized production parameters are a stirring speed of 36,000 rpm (maximum speed) and a production time of 5 min. A further reduction in processing time might be possible with a rotor with ultrafine slit size, i.e., 0.5 mm. The droplet size of the emulsion produced by high speed stirring is slightly larger than droplet sizes obtained by high pressure homogenization. However, the differences in size can be expected to have no influence on the in vivo efficacy of the emulsions. Thus, high speed stirring was found to be a highly effective method for the production of nanoemulsions. The process is fast, cost-effective and can be used for large scale production.
Keywords: Nanoemulsions; High speed stirring; High pressure homogenization; Rotor-stator;
Development of a tumor tissue-mimicking model with endothelial cell layer and collagen gel for evaluating drug penetration by Noboru Sasaki; Clemens Bos; Jean-Michel Escoffre; Gert Storm; Chrit Moonen (118-122).
Display OmittedThe endothelial cells of vessels, the interstitial matrix and the distance between the tumor cells and vessels, are the major penetration barriers for intravenously administered anticancer drugs in reaching tumor cells after intravenous injection. The availability of a tumor tissue-mimicking model that includes both the endothelial cell layer and the extracellular matrix would be beneficial to assess drug penetration in early stages of drug development. Here, we propose a novel in vitro model for studying the above mentioned barriers. Human umbilical vein endothelial cells were cultured as a single layer on a collagen type-I coated permeable cell culture insert. After culturing for five days, the insert was superimposed on collagen type-I gel containing cancer cells. The system was evaluated for assessing penetration-enhancement by ultrasound triggered microbubble cavitation. Our model allowed visualization of the penetration distance of a model drug (fluorescein isothiocyanate – Dextran 500000-conjugated, FD500) from the endothelial cell layer into the cancer cell containing collagen matrix upon different sonication treatments. Initial results showed that the model allows the visualization of drug penetration and that the endothelial cell layer is affecting this. The presented in vitro model aims to mimic vessels and stromal tissue in cancer, and thus can aid in the assessment of drug penetration in the case of tumor-targeted drug delivery, and in the reduction and refinement of animal studies.
Keywords: Drug penetration; Endothelial layer; Extracellular matrix; Tissue-mimicking model;
Formulation and characterization of microspheres loaded with imatinib for sustained delivery by F. Ramazani; W. Chen; C.F. Van Nostrum; G. Storm; F. Kiessling; T. Lammers; W.E. Hennink; R.J. Kok (123-130).
Display OmittedThe aim of this study was the development of imatinib-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with high loading efficiency which can afford continuous release of imatinib over a prolonged period of time. Imatinib mesylate loaded PLGA microspheres with a size of 6–20 μm were prepared by a double emulsion (W1/O/W2) method using dichloromethane as volatile solvent. It was found that the microspheres were spherical with a non-porous surface; imatinib loading efficiency (LE) was highly dependent on the pH of the external water phase (W2). By increasing the pH of W2 phase above the highest pK a of imatinib (pK a 8.1), at which imatinib is mainly uncharged, the LE increased from 10% to 90% (pH 5.0 versus pH 9.0). Conversely, only 4% of its counter ion, mesylate, was retained in the microspheres at the same condition (pH 9.0). Since mesylate is highly water soluble, it is unlikely that it partitions into the organic phase.We demonstrated, using differential scanning calorimetry (DSC), that imatinib was molecularly dispersed in the polymeric matrix at loadings up to 8.0%. At higher drug loading, imatinib partially crystallized in the matrix. Imatinib microspheres released their cargo during three months by a combination of diffusion through the polymer matrix and polymer erosion.In conclusion, we have formulated imatinib microspheres with high LE and LC. Although we started with a double emulsion of imatinib mesylate, the obtained microspheres contained imatinib base which was mainly molecularly dispersed in the polymer matrix. These microspheres release imatinib over a 3-month period which is of interest for local treatment of cancer.
Keywords: Imatinib mesylate; Double emulsion (W1/O/W2); PLGA microspheres; log D; Loading efficiency; drug release;