Multiple Roles of Chitosan in Mucosal Drug Delivery: An Updated Review.

Chitosan (CS) is a linear polysaccharide obtained by the deacetylation of chitin, which, after cellulose, is the second biopolymer most abundant in nature, being the primary component of the exoskeleton of crustaceans and insects. Since joining the pharmaceutical field, in the early 1990s, CS attracted great interest, which has constantly increased over the years, due to its several beneficial and favorable features, including large availability, biocompatibility, biodegradability, non-toxicity, simplicity of chemical modifications, mucoadhesion and permeation enhancer power, joined to its capability of forming films, hydrogels and micro- and nanoparticles. Moreover, its cationic character, which renders it unique among biodegradable polymers, is responsible for the ability of CS to strongly interact with different types of molecules and for its intrinsic antimicrobial, anti-inflammatory and hemostatic activities. However, its pH-dependent solubility and susceptibility to ions presence may represent serious drawbacks and require suitable strategies to be overcome. Presently, CS and its derivatives are widely investigated for a great variety of pharmaceutical applications, particularly in drug delivery. Among the alternative routes to overcome the problems related to the classic oral drug administration, the mucosal route is becoming the favorite non-invasive delivery pathway. This review aims to provide an updated overview of the applications of CS and its derivatives in novel formulations intended for different methods of mucosal drug delivery.

Preparation, Characterization and Evaluation of the Anti-Inflammatory Activity of Epichlorohydrin-ß-Cyclodextrin/Curcumin Binary Systems Embedded in a Pluronic®/Hyaluronate Hydrogel.

Curcumin (Cur) is an anti-inflammatory polyphenol that can be complexed with polymeric cyclodextrin (CD) to improve solubility and bioavailability. The aim of the present work was to prepare a CurCD hydrogel to treat inflammatory skin conditions. Epichlorohydrin-ß-CD (EpißCD) was used as polymeric CD. To characterize the binary system, solid-state and in-solution studies were performed. Afterwards, an experimental design was performed to optimize the hydrogel system. Finally, the CurEpißCD hydrogel system was tested for anti-inflammatory activity using a HaCat psoriasis cell model. Co-grinded Cur/EpißCD binary system showed a strong interaction and Curcumin solubility was much improved. Its combination with Pluronic® F-127/hyaluronate hydrogel demonstrated an improvement in release rate and Curcumin permeation. After testing its anti-inflammatory activity, the system showed a significant reduction in IL-6 levels. Hydrogel-containing CurEpißCD complex is a great alternative to treat topical inflammatory diseases.

Cyclodextrin complexation highly enhances efficacy of arylsulfonylureido benzenesulfonamide carbonic anhydrase inhibitors as a topical antiglaucoma agents.

Two new sulfonamides incorporating arylsulfonylureido moieties were complexed with gamma cyclodextrin (γ-CD), hydroxypropyl-gamma cyclodextrin (HPγ-CD), hydroxypropyl-beta cyclodextrin (HPß-CD) and hydroxyethyl-beta cyclodextrin (HEß-CD) in order to obtain drug formulations with effective topical intraocular pressure (IOP) lowering effects, in an animal model of glaucoma. The HPγ-CD was the best solubilizing agent for the two sulfonamides and its complexes were characterized in detail and administered to rabbits with eye hypertension of 45-50 mmHg. The peak IOP lowering was observed after 1h post-administration and was of 36-37 mmHg. A low IOP pressure (of around-35 mmHg) was then maintained for the next 24h post-administration, which has not been observed before with any IOP lowering drug.

Fast analysis of glibenclamide and its impurities: quality by design framework in capillary electrophoresis method development.

A fast capillary zone electrophoresis method for the simultaneous analysis of glibenclamide and its impurities (I(A) and I(B)) in pharmaceutical dosage forms was fully developed within a quality by design framework. Critical quality attributes were represented by I(A) peak efficiency, critical resolution between glibenclamide and I(B), and analysis time. Experimental design was efficiently used for rapid and systematic method optimization. A 3(5)//16 symmetric screening matrix was chosen for investigation of the five selected critical process parameters throughout the knowledge space, and the results obtained were the basis for the planning of the subsequent response surface study. A Box-Behnken design for three factors allowed the contour plots to be drawn and the design space to be identified by introduction of the concept of probability. The design space corresponded to the multidimensional region where all the critical quality attributes reached the desired values with a degree of probability π ≥ 90%. Under the selected working conditions, the full separation of the analytes was obtained in less than 2 min. A full factorial design simultaneously allowed the design space to be validated and method robustness to be tested. A control strategy was finally implemented by means of a system suitability test. The method was fully validated and was applied to real samples of glibenclamide tablets.

Development of a chitosan-derivative micellar formulation to improve celecoxib solubility and bioavailability.

CONTEXT: Celecoxib is an anti-inflammatory drug, specific inhibitor of COX-2, classified as a BCS class II compound due to its very low aqueous solubility (3 µg/mL) and good permeability. OBJECTIVE: An innovative micellar formulation of celecoxib has been developed to increase its solubility and, consequently, its oral bioavailability. MATERIALS AND METHODS: Quaternary-ammonium-palmitoyl-glycol-chitosan (GCPQ) was selected as carrier, due to its micelle-forming ability joined to its solubilizing and enhancer properties towards hydrophobic drugs. A Doehlert design was applied to optimize the drug solubilizing efficiency of the micellar formulation. Tested factors were GCPQ concentration and time and power of probe sonication during micelles formation; the response to maximize was the celecoxib solubility. RESULTS: The response-surface study allowed a thorough investigation of the effect of factors variations on the response over the considered experimental domain and identification of the best variable combination in order to maximize the desired improvement in drug solubility. The optimized micellar formulation (GCPQ 4.5 mg/mL; 25 min at 60% power of probe sonication) enabled an about 60-fold increase in celecoxib aqueous solubility. The optimized formulation, tested in vivo in mice by the writhing test, allowed a statistically significant shortening (p < 0.05) of the pain alleviation onset and a more intense effect (p < 0.05) with respect to the celecoxib aqueous suspension obtained by the commercial formulation. CONCLUSIONS: The results proved that the developed GCPQ micellar formulation is a valuable approach for improving the therapeutic effectiveness of celecoxib.

Development of Oral Tablets of Nebivolol with Improved Dissolution Properties, Based on Its Combinations with Cyclodextrins.

New oral tablets of nebivolol have been developed aiming to improve, by cyclodextrin (CD) complexation, its low solubility/dissolution properties-the main reason behind its poor/variable oral bioavailability. Phase-solubility studies, performed using ßCD and highly-soluble ßCD-derivatives, indicated sulfobutylether-ßCD (SBEßCD) as the best solubilizing/complexing agent. Solid drug-SBEßCD systems were prepared by different methods and characterized for solid-state and dissolution properties. The coevaporated product was chosen for tablet development since it provided the highest dissolution rate (100% increase in dissolved drug at 10 min) and almost complete drug amorphization/complexation. The developed tablets reached the goal, allowing us to achieve 100% dissolved drug at 60 min, compared to 66% and 64% obtained, respectively, with a reference tablet without CD and a commercial tablet. However, the percentage dissolved after 10 min from such tablets was only 10% higher than the reference. This was ascribed to the potential binding/compacting abilities of SBEßCD, reflected in the greater hardness and longer disintegration times of the new tablets than the reference (7.64 vs. 1.06 min). A capsule formulation with the same composition of nebivolol-SBEßCD tablets showed about a 90% increase in dissolved drug after 5 min compared to the reference tablet, and reached 100% dissolved drug after only 20 min.

Taste Masking of Dexketoprofen Trometamol Orally Disintegrating Granules by High-Shear Coating with Glyceryl Distearate.

Orally disintegrating granules (ODGs) are a pharmaceutical form commonly used for the administration of NSAIDs because of their easy assumption and fast dispersion. The development of ODGs is not easy for drugs like dexketoprofen trometamol (DXKT), which have a bitter and burning taste. In this work, high-shear coating (HSC) was used as an innovative technique for DKXT taste masking. This study focused on coating DXKT granules using the HSC technique with a low-melting lipid excipient, glyceryl distearate (GDS). The HSC technique allowed for the coating to be developed through the thermal rise resulting from the friction generated by the granules movement inside the equipment, causing the coating excipient to soften. The design of the experiment was used to find the best experimental coating conditions in order to gain effective taste masking by suitably reducing the amount of drug released in the oral cavity. The influence of the granule dimensions was also investigated. Coating effectiveness was evaluated using a simulated saliva dissolution test. It was found that low impeller speed (300 rpm) and a 20% coating excipient were effective in suitably reducing the drug dissolution rate and then in taste masking. The coated granules were characterized for their morphology and solid-state properties by SEM, BET, XRPD, DSC, and NIR analyses. A human taste panel test confirmed the masking of DXKT taste in the selected batch granules.

Development of a Hydroxypropyl-ß-Cyclodextrin-Based Liquid Formulation for the Oral Administration of Propranolol in Pediatric Therapy.

Propranolol (PPN) is widely used in children to treat various cardiovascular diseases. The availability of a suitable PPN solution should avoid recourse to extemporaneous preparations of unknown/limited stability, as commonly made in hospital pharmacies. However, the development of pediatric PPN solutions is hindered by their instability to light and stability at pH ≈ 3, bitter taste, and the need to improve palatability and avoid co-solvents, flavoring agents, or preservatives that are potentially toxic. In this study, cyclodextrin (CD) complexation has been exploited to develop a safe, stable, and palatable oral pediatric solution of PPN. An initial screening among various CDs allowed us to select HPßCD for its good complexing ability and no toxicity. Drug-HPßCD physical mixtures or co-ground systems (1:1 or 1:2 mol:mol) were used to prepare 0.2% w/v drug solutions. Photo stability studies evidenced the protective effect of HPßCD, revealing a reduction of up to 75% in the drug degradation rate after 1 h of exposure to UV radiation. Storage stability studies showed unchanged physical-chemical properties and almost constant drug concentration after 6 months and under accelerated conditions (40 °C), despite the less aggressive pH (≈5.5) of the solution. The electronic tongue test proved that the HPßCD taste-masking properties improved the formulation palatability, with a 30% reduction in drug bitterness.

Design, Evaluation and Comparison of Nanostructured Lipid Carriers and Chitosan Nanoparticles as Carriers of Poorly Soluble Drugs to Develop Oral Liquid Formulations Suitable for Pediatric Use.

There is a serious need of pediatric drug formulations, whose lack causes the frequent use of extemporaneous preparations obtained from adult dosage forms, with consequent safety and quality risks. Oral solutions are the best choice for pediatric patients, due to administration ease and dosage-adaptability, but their development is challenging, particularly for poorly soluble drugs. In this work, chitosan nanoparticles (CSNPs) and nanostructured lipid carriers (NLCs) were developed and evaluated as potential nanocarriers for preparing oral pediatric solutions of cefixime (poorly soluble model drug). The selected CSNPs and NLCs showed a size around 390 nm, Zeta-potential > 30 mV, and comparable entrapment efficiency (31-36%), but CSNPs had higher loading efficiency (5.2 vs. 1.4%). CSNPs maintained an almost unchanged size, homogeneity, and Zeta-potential during storage, while NLCs exhibited a marked progressive Zeta-potential decrease. Drug release from CSNPs formulations (differently from NLCs) was poorly affected by gastric pH variations, and gave rise to a more reproducible and controlled profile. This was related to their behavior in simulated gastric conditions, where CSNPs were stable, while NLCs suffered a rapid size increase, up to micrometric dimensions. Cytotoxicity studies confirmed CSNPs as the best nanocarrier, proving their complete biocompatibility, while NLCs formulations needed 1:1 dilution to obtain acceptable cell viability values.

Development and characterization of niosomal formulations of doxorubicin aimed at brain targeting.

PURPOSE: The aim of the present work was the development and characterization of a niosomal formulation functionalized with the glucose-derivative N-palmitoylglucosamine (NPG) to obtain a potential brain targeted delivery system for the anticancer agent doxorubicin. METHODS: Five different methods have been examined for vesicle preparation. Light scattering and transmission electron microscopy were used for vesicle characterization, in terms of mean size, homogeneity and Zeta potential, and selection of the best composition and preparation conditions for developing NPG-functionalized niosomes. Drug entrapment efficiency was determined after separation of loaded from unloaded drug by size exclusion chromatography or dialysis. Preliminary in vivo studies were performed on rats, injected i.v. with 12 mg/kg of doxorubicin as commercial solution (Ebewe, 2 mg/mL) or NPG-niosomal formulation. Drug amounts in the blood and in the major organs of the animals, sacrificed 60 min post injection, were determined by HPLC. RESULTS: The selected formulation consisted in Span:cholesterol:Solulan:NPG (50:40:10:10 mol ratio) vesicles obtained by thin-layer evaporation, leading to homogeneous vesicles of less than 200 nm diameter. This formulation was used for preparation of NPG-niosomes loaded with doxorubicin (mean size 161±4 nm, encapsulation efficacy 57.8±1.8%). No significant changes (P>0.05) in vesicle dimensions, Zeta potential or entrapment efficiency were observed after six months storage at room temperature, indicative of good stability. I.v. administration to rats of the NPG-niosomal formulation allowed for reducing drug accumulation in the heart and keeping it longer in the blood circulation with respect to the commercial formulation. Moreover, a doxorubicin brain concentration of 2.9±0.4 µg/g was achieved after 60 min, while the commercial solution yielded undetectable drug brain concentrations (<0.1 µg/g). CONCLUSIONS: The developed NPG-niosomal formulation gave rise to stable, nano-sized vesicles, able to improve doxorubicin brain delivery. Positive results of preliminary in vivo studies require future pharmacokinetic studies to gain more insight into the mechanism of drug transport of functionalized niosomes.

New solid self-microemulsifying systems to enhance dissolution rate of poorly water soluble drugs.

CONTEXT: An adequate drug dissolution behavior is essential for the therapeutic effectiveness of all solid dosage forms. OBJECTIVE: To develop a new solid self-micro-emulsifying drug delivery system (S-SMEDDS) to improve the dissolution properties of poorly water-soluble drugs, such as glyburide. METHODS: Liquid self-micro-emulsifying drug delivery systems (SMEDDS) consisted of Labrafac-Hydro(®), Tween(®) 20, Transcutol(®), and drug. S-SMEDDS were prepared by adsorption of SMEDDS onto different adsorbents; the obtained powders were evaluated for flow, compactability and liquid-retention potential. The reconstitution ability of S-SMEDDS into SMEDDS by re-dispersion in water was assessed. Tablets, prepared by direct compression of selected S-SMEDDS, were characterized for technological properties and dissolution behavior. RESULTS: Neusilin US2 was selected as the most effective adsorbent, based on its better flow and compacting properties, greater surface area and mesoporosity. The significantly higher (P < 0.001) drug dissolution rate from S-SMEDDS-based tablets than from commercial tablets was ascribed to enhanced wetting and surface area of drug, finely distributed onto the hydrophilic adsorbent, and, above all, to the already drug dissolved form in the SMEDDS system. Properties, drug content and dissolution from S-SMEDDS tablets were unchanged after 25°C and 60% RH six-month storage. CONCLUSIONS: The developed tablets showed the advantages of SMEDDS, allowing a strong improvement of drug dissolution, together with increased physical and chemical stability.

Role of Cyclodextrins and Drug Solid State Properties on Flufenamic Acid Dissolution Performance from Tablets.

Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug characterised by a low solubility and problems of variable dissolution rate and bio-inequivalence. Different FFA batches, obtained by different suppliers, showed different powder characteristics (particle size, shape and surface properties) that may affect its dissolution behaviour from solid dosage forms. Aim of this work was the improvement of FFA solubility and dissolution rate by the use of cyclodextrins (CDs) and the obtainment of an effective tablet formulation by direct compression. Several CDs have been tested, both in solution and in solid state and several binary systems drug-CDs have been obtained with different techniques, with the scope to select the most effective system. Grinding technique with randomly methylated-ß-cyclodextrin (RAMEB) was the only one that allowed the complete drug amorphization, together with the highest improvement in drug dissolution rate, and was then selected for tablets formulation. Conventional and immediate release tablets were obtained and fully characterised for technological properties. In both cases an improved and well reproducible drug dissolution performance was obtained, independently from the FFA supplier and thus no more affected by the differences observed between the original FFA crystalline samples.

Development and Characterization of Cyclodextrin-Based Nanogels as a New Ibuprofen Cutaneous Delivery System.

Nanogels combine the properties of hydrogels and nanocarrier systems, resulting in very effective drug delivery systems, including for cutaneous applications. Cyclodextrins (CDs) have been utilised to enhance the nanogels' loading ability towards poorly soluble drugs and promote/sustain drug release. However, formation of CD-based nanogels requires the use of specially modified CDs, or of crosslinking agents. The aim of this work was to develop a CD-based nanogel to improve the cutaneous delivery of ibuprofen by using the soluble ß-cyclodextrin/epichlorohydrin polymer (EPIßCD) without adding any potentially toxic crosslinker. The use of EPIßCD enabled increasing ibuprofen loading due to its complexing/solubilizing power towards the poorly soluble drug and prolonging drug release over time due to the nanogel formation. DLS analysis proved that EPIßCD allowed the formation of nanostructures ranging from 60 up to 400 nm, depending on the gelling agent type and the gel preparation method. EPIßCD replacement with monomeric HPßCD did not lead in any case to nanogel formation. Permeation experiments using skin-simulating artificial membranes proved that the EPIßCD-based nanogel enhanced ibuprofen solubility and release, increasing its permeation rate up to 3.5 times, compared to a reference formulation without CD and to some commercial gel formulations, and also assured a sustained release. Moreover, EPIßCD replacement with HPßCD led to a marked increase in drug solubility and initial release rate, but did not provide a prolonged release due to the lack of a nano-matrix structure controlling drug diffusion.

Evaluation and Comparison of Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) as Vectors to Develop Hydrochlorothiazide Effective and Safe Pediatric Oral Liquid Formulations.

The aim of this study was the optimization of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in terms of physicochemical and biopharmaceutical properties, to develop effective and stable aqueous liquid formulations of hydrochlorothiazide, suitable for paediatric therapy, overcoming its low-solubility and poor-stability problems. Based on solubility studies, Precirol® ATO5 and Transcutol® HP were used as solid and liquid lipids, respectively. The effect of different surfactants, also in different combinations and at different amounts, on particle size, homogeneity and surface-charge of nanoparticles was carefully investigated. The best formulations were selected for drug loading, and evaluated also for entrapment efficiency and release behaviour. For both SLN and NLC series, the use of Gelucire® 44/14 as surfactant rather than PluronicF68 or Tween® 80 yielded a marked particle size reduction (95-75 nm compared to around 600-400 nm), and an improvement in entrapment efficiency and drug release rate. NLC showed a better performance than SLN, reaching about 90% entrapped drug (vs. 80%) and more than 90% drug released after 300 min (vs. about 65%). All selected formulations showed good physical stability during 6-month storage at 4 °C, but a higher loss of encapsulated drug was found for SLNs (15%) than for NLCs (<5%). Moreover, all selected formulations revealed the absence of any cytotoxic effect, as assessed by a cell-viability test on Caco-2 cells and are able to pass the intestinal epithelium as suggested by Caco-2 uptake experiments.

Development of a Near Infrared Spectroscopy method for the in-line quantitative bilastine drug determination during pharmaceutical powders blending.

The Food and Drug Administration (FDA)'s guidelines and the Process Analytical Technology (PAT) approach conceptualize the idea of real time monitoring of a process, with the primary objective of improvement of quality and also of time and resources saving. New instruments are needed to perform an efficient PAT process control and Near Infrared Spectroscopy (NIRS), thanks to its rapid and drastic development of last years, could be a very good choice, in virtue of its high versatility, speed of analysis, non-destructiveness and absence of sample chemical treatment. This work was aimed to develop a NIR analytical method for bilastine assay in powder mixtures for direct compression. In particular, the use of NIR instrumentation should allow to control the bilastine concentration and the whole blending process, assuring the achievement of a homogeneous blend. The commercial tablet formulation of bilastine was particularly suitable for this purpose, due to its simple composition (four excipients) and direct compression manufacturing process. Calibration and validation set were prepared according to a Placket-Burman experimental design and acquired with a miniaturized NIR in-line instrument (MicroNIR by Viavi Solution Inc.). Chemometric was applied to optimize information extraction from spectra, by subjecting them to a Standard Normal Variate (SNV) and a Savitzky-Golay second derivative pre-treatment. This spectra pre-treatment, combined with the most suitable wavelength interval (resulted between 1087 and 1217 nm), enabled to obtain a Partial Least Square (PLS) model with a good predictive ability. The selected model, tried on laboratory and production batches, provided in both cases good assay predictions. Results were confirmed by traditional HPLC (High Performance Liquid Chromatography) API (Active Pharmaceutical Ingredient) content uniformity test on the final product.

Development of a Cyclodextrin-Based Mucoadhesive-Thermosensitive In Situ Gel for Clonazepam Intranasal Delivery.

A thermosensitive, mucoadhesive in-situ gel for clonazepam (CLZ) intranasal delivery was developed, which aimed to achieve prolonged in-situ residence and controlled drug release, overcoming problems associated with its oral or parenteral administration. Poloxamer was selected as a thermosensitive polymer and chitosan glutamate and sodium hyaluronate as mucoadhesive and permeation enhancer. Moreover, randomly methylated ß-Cyclodextrin (RAMEB) was used to improve the low drug solubility. A screening DoE was applied for a systematic examination of the effect of varying the formulation components proportions on gelation temperature, gelation time and pH. Drug-loaded gels at different clonazepam-RAMEB concentrations were then prepared and characterized for gelation temperature, gelation time, gel strength, mucoadhesive strength, mucoadhesion time, and drug release properties. All formulations showed suitable gelation temperature (29-30.5 °C) and time (50-65 s), but the one with the highest drug-RAMEB concentration showed the best mucoadhesive strength, longest mucoadhesion time (6 h), and greatest release rate. Therefore, it was selected for cytotoxicity and permeation studies through Caco-2 cells, compared with an analogous formulation without RAMEB and a drug solution. Both gels were significantly more effective than the solution. However, RAMEB was essential not only to promote drug release, but also to reduce drug cytotoxicity and further improve its permeability.

Combined Use of Cyclodextrins and Amino Acids for the Development of Cefixime Oral Solutions for Pediatric Use.

Cefixime (CEF) is a cephalosporin included in the WHO Model List of Essential Medicines for Children. Liquid formulations are considered the best choice for pediatric use, due to their great ease of administration and dose-adaptability. Owing to its very low aqueous solubility and poor stability, CEF is only available as a powder for oral suspensions, which can lead to reduced compliance by children, due to its unpleasant texture and taste, and possible non-homogeneous dosage. The aim of this work was to develop an oral pediatric CEF solution endowed with good palatability, exploiting the solubilizing and taste-masking properties of cyclodextrins (CDs), joined to the use of amino acids as an auxiliary third component. Solubility studies indicated sulfobutylether-ß-cyclodextrin (SBEßCD) and Histidine (His) as the most effective CD and amino acid, respectively, even though no synergistic effect on drug solubility improvement by their combined use was found. Molecular Dynamic and 1H-NMR studies provided insight into the interactions of binary CEF:His and ternary CEF:His:SBEßCD systems used to prepare CEF solutions, which resulted stable and maintained unchanged antimicrobial activity during the two-weeks-use in therapy. The ternary solution was superior in terms of more tolerable pH (5.6 vs. 4.7) and better palatability, being resulted completely odorless by a panel test.

Improvement of Butamben Anesthetic Efficacy by the Development of Deformable Liposomes Bearing the Drug as Cyclodextrin Complex.

This work was aimed at enhancing butamben (BTB) anesthetic efficacy by the "drug-in cyclodextrin (CD)-in deformable liposomes" strategy. In the study, phase-solubility studies with natural (α-, ß-, γ-) and derivative (hydroxypropyl-α-and ß-, sulfobutylether-ß, methyl-ß) CDs evidenced the highest BTB affinity for ßCD and its derivatives and indicated methyl-ßCD (RAMEB) as the best carrier. Drug-RAMEB complexes were prepared by different techniques and were characterized for solid-state and dissolution properties. The best BTB-RAMEB product was chosen for entrapment in the aqueous core of deformable liposomes containing stearylamine, either alone or with sodium cholate, as edge activators. Double-loaded (DL) liposomes, bearing the lipophilic drug (0.5% w/v) in the bilayer and its hydrophilic RAMEB complex (0.5% w/v) in the aqueous core, were compared to single-loaded (SL) liposomes bearing 1% w/v plain drug in the bilayer. All vesicles showed homogeneous dimensions (i.e., below 300 nm), high deformability, and excellent entrapment efficiency. DL-liposomes were more effective than SL ones in limiting drug leakage (<5% vs. >10% after a 3 months storage at 4 °C). In vivo experiments in rabbits proved that all liposomal formulations significantly (p < 0.05) increased the intensity and duration of drug anesthetic action compared to its hydroalcoholic solution; however, DL liposomes were significantly (p < 0.05) more effective than SL ones in prolonging BTB anesthetic effect, owing to the presence of the drug-RAMEB complex in the vesicle core, acting as a reservoir. DL liposomes containing both edge activators were found to have the best performance.

Liposomal formulations of prilocaine: effect of complexation with hydroxypropyl-ß-cyclodextrin on drug anesthetic efficacy.

A combined strategy, based on cyclodextrin complexation and loading in liposomes, has been investigated to develop a new delivery system with improved therapeutic activity of the local anesthetic, prilocaine (PRL). In order to evaluate the actual effectiveness and advantages of this approach compared to the traditional drug-in-liposome one, four different liposomal formulations were prepared: (1) liposomes loaded with PRL base as complex with hydroxypropyl-ß-cyclodextrin (HP CD) in the aqueous phase; (2) liposomes loaded with PRL hydrochloride in the aqueous phase; (3) liposomes loaded with PRL base in the lipophilic phase; and (4) "double-loaded" liposomes, containing free PRL base in the membrane bilayer and its HP CD complex in the aqueous compartment. All batches were characterized for particle size, charge, deformability, and entrapment efficiency from using, respectively, light scattering, extrusion, and dialysis techniques, while the anesthetic effect was evaluated in vivo on Guinea pigs, according to the test of dorsal muscle contraction. All drug liposomal dispersions showed enhanced analgesic duration with respect to the corresponding aqueous solutions, but significant differences were observed between the different formulations. In particular, cyclodextrin complexation not only allowed an efficient encapsulation of PRL base in the aqueous vesicle core, but also increased the anesthetic effect duration and reduced the initial lag time, in comparison with the corresponding formulations containing, respectively, free PRL in the lipophilic phase or PRL hydrochloride in the aqueous vesicle core. The technique of double loading was the most effective, giving rise to the shortest onset time and longest duration of anesthetic effect.

Development of a new delivery system consisting in 'drug-in cyclodextrin-in PLGA nanoparticles'.

A combined approach based on drug cyclodextrin (CD) complexation and loading into PLGA nanoparticles (NP) has been developed to improve oxaprozin therapeutic efficiency. This strategy exploits the solubilizing and stabilizing properties of CDs and the prolonged-release and targeting properties of PLGA NPs. Drug-loaded NPs, prepared by double-emulsion, were examined for dimensions, zeta-potential and entrapment efficiency. Solid-state studies demonstrated the absence of drug-polymer interactions and assessed the amorphous state of the drug-CD complex loaded into NPs. Drug release rate from NPs was strongly influenced by the presence and kind of CD used. The percentage released at 24 h varied from 16% (plain drug-loaded NPs) to 50% (drug-betaCD-loaded NPs) up to 100% (drug-methylbetaCD-loaded NPs). This result suggests the possibility of using CD complexation not only to promote, but also to regulate drug release rate from NPs, by selecting the proper type of CD or CD combination.