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.

Technical Evaluation of a New Medical Device Based on Rigenase in the Treatment of Chronic Skin Lesions.

Chronic wound is characterized by slow healing time, persistence, and abnormal healing progress. Therefore, serious complications can lead at worst to the tissue removal. In this scenario, there is an urgent need for an ideal dressing capable of high absorbency, moisture retention and antimicrobial properties. Herein we investigate the technical properties of a novel advanced non-woven triple layer gauze imbibed with a cream containing Rigenase, an aqueous extract of Triticum vulgare used for the treatment of skin injuries. To assess the applicability of this system we analyzed the dressing properties by wettability, dehydration, absorbency, Water Vapor Transmission Rate (WVTR), lateral diffusion and microbiological tests. The dressing showed an exudate absorption up to 50%. It created a most environment allowing a proper gaseous exchange as attested by the WVTR and a controlled dehydration rate. The results candidate the new dressing as an ideal medical device for the treatment of the chronic wound repairing process. It acts as a mechanical barrier providing a good management of the bacterial load and proper absorption of abundant wound exudate. Finally, its vertical transmission minimizes horizontal diffusion and side effects on perilesional skin as maceration and bacterial infection.

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.

Researching the level of agreement among experts on terms used to describe wounds: An international study.

Establishing a common language that allows univocal and objective communication in describing wounds and their healing is of utmost importance in defining the diagnostic hypothesis and proper wound management. To measure the level of agreement on the description of wounds, an international study was performed among experts of different professional backgrounds on several common terms used to describe ulcerative lesions. A panel of 27 wound care experts anonymously completed a multiple-choice questionnaire on 100 images of 50 ulcerative lesions. The participants were asked to describe each image using a set of pre-defined terms. An expert data analyst interpreted the questionnaires to map the level of agreement on the used terminology. Our findings show a very low level of agreement among experts in using the proposed terminology to describe the wound bed, the wound edge, and the surrounding skin conditions. Efforts should be planned to find a consensus on the correct use of terminology for wound description. To this aim, partnership, consensus, and agreement with educators in medicine and nursing are necessary.

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.

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.

4-Heteroaryl Substituted Amino-3,5-Dicyanopyridines as New Adenosine Receptor Ligands: Novel Insights on Structure-Activity Relationships and Perspectives.

A new set of amino-3,5-dicyanopyridines was synthesized and biologically evaluated at the adenosine receptors (ARs). This chemical class is particularly versatile, as small structural modifications can influence not only affinity and selectivity, but also the pharmacological profile. Thus, in order to deepen the structure-activity relationships (SARs) of this series, different substituents were evaluated at the diverse positions on the dicyanopyridine scaffold. In general, the herein reported compounds show nanomolar binding affinity and interact better with both the human (h) A1 and A2A ARs than with the other subtypes. Docking studies at hAR structure were performed to rationalize the observed affinity data. Of interest are compounds 1 and 5, which can be considered as pan ligands as binding all the ARs with comparable nanomolar binding affinity (A1AR: 1, Ki = 9.63 nM; 5, Ki = 2.50 nM; A2AAR: 1, Ki = 21 nM; 5, Ki = 24 nM; A3AR: 1, Ki = 52 nM; 5, Ki = 25 nM; A2BAR: 1, EC50 = 1.4 nM; 5, EC50 = 1.12 nM). Moreover, these compounds showed a partial agonist profile at all the ARs. This combined AR partial agonist activity could lead us to hypothesize a potential effect in the repair process of damaged tissue that would be beneficial in both wound healing and remodeling.

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.

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.

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.

Development of a stable oral pediatric solution of hydrochlorothiazide by the combined use of cyclodextrins and hydrophilic polymers.

Hydrochlorothiazide (HCT) is widely used in pediatrics for hypertension management. Due to the lack of pediatric commercial forms, community or hospital pharmacies generally prepare HCT extemporaneous pediatric suspensions by dispersing in water a portion of a crushed tablet or the drug powder; however, any dose or stability control is usually done on these preparations. Obtaining stable HCT solutions is very challenging, due to its low water-solubility and pH-dependent degradation. The aim of this work was to develop a stable 2 mg/mL-HCT oral pediatric solution without using co-solvents. Combined use of cyclodextrins (CD) and hydrophilic polymers was exploited to improve poor HCT solubility and stability. HPßCD and SBEßCD were selected, considering their safe toxicological profiles, while PVP resulted the best among the tested polymers. Low PVP concentrations (0.2-1.0%) improved the solubilizing efficiency of both CDs, allowing to reach the prefixed HCT concentration. Different CD-PVP concentrations were used to prepare several 2 mg/mL-HCT solutions in pH 5.5 buffer. The best stability was shown by solutions containing the highest SBEßCD concentration (25 mM), which allowed a 3-months stability at 4 °C. In vivo studies on rats showed that such formulation allowed a more pronounced and more reproducible diuretic effect than the corresponding HCT suspension.

Characterization and evaluation of the performance of different calcium and magnesium salts as excipients for direct compression.

The performance of a series of inorganic salts as direct compression excipients was systematically evaluated. The physical-chemical and technological properties of the different salts were investigated in terms of crystalline/amorphous state, morphology, granulometry, apparent/tapped density, specific surface area, flowability, compressibility, dilution and distribution coefficients. To achieve a comprehensive evaluation of the performance of the different salts, the data obtained by the various analyses were normalized, giving a score to each excipient for each evaluated property/parameter. Statistical elaboration (JMP software) of the full dataset provided a final ranking of the powders based on their effectiveness as direct compression excipients. The salt emerged as the best was used to prepare direct-compression tablets, using cefixime as model drug, by modifying the composition of marketed tablets. A significant improvement of the mechanical properties of the new tablets was observed, compared to the marketed ones, with a crushing strength increase of over 30%, without variations of the drug dissolution profile. Even though the resulted ranking cannot have an absolute value, being the behavior of the different excipients susceptible to the kind of drug and other formulation excipients, the proposed approach can provide a useful model for a systematic evaluation and comparison of potentially similar excipients.

Design, characterization and in vivo evaluation of nanostructured lipid carriers (NLC) as a new drug delivery system for hydrochlorothiazide oral administration in pediatric therapy.

The hydrochlorothiazide (HCT) low solubility and permeability give rise to limited and variable bioavailability; its low stability makes it difficult to develop stable aqueous liquid formulations; its low dose makes the achievement of a homogeneous drug distribution very difficult. Thus, the aim of this study was to investigate the effectiveness of a strategy based on the development of nanostructured lipid carriers (NLC) as an innovative oral pediatric formulation of HCT with improved therapeutic efficacy. The performance of various synthetic and natural liquid lipids was examined and two different preparation methods were employed, i.e. homogenization-ultrasonication (HU) and microemulsion (ME), in order to evaluate their influence on the NLC properties in terms of size, polydispersity index, ζ-potential, entrapment efficiency, gastric stability, and drug release properties. Precirol®ATO5 was used as solid lipid and Tween®80 and Pluronic®F68 as surfactants, formerly selected in a previous study focused on the development of HCT-solid lipid nanoparticles (SLNs). The presence of Pluronic®F68 did not allow ME formation. On the contrary, using Tween®80, the ME method enabled a higher entrapment efficiency than the HU. Regardless of the preparation method, NLCs exhibited great entrapment efficiency values clearly higher than previous SLNs. Moreover, NLC-ME formulations provided a prolonged release, which lasted for 6 h. In particular, NLC-ME containing Tween®20 as Co-Surfactant showed the best performances, giving rise to a complete drug release, never achieved with previous SLN formulations, despite their successful results. In vivo studies on rats confirmed these results, displaying their best diuretic profile. Moreover, all HCT-loaded NLC formulations showed higher stability than the corresponding SLNs.

A preliminary study for the development and optimization by experimental design of an in vitro method for prediction of drug buccal absorption.

The work was aimed at developing an in vitro method able to provide rapid and reliable evaluation of drug absorption through buccal mucosa. Absorption simulator apparatus endowed with an artificial membrane was purposely developed by experimental design. The apparent permeation coefficient (Papp) through excised porcine buccal mucosa of naproxen, selected as model drug, was the target value to obtain with the artificial membrane. The multivariate approach enabled systematic evaluation of the effect on the response (Papp) of simultaneous variations of the variables (kind of lipid components for support impregnation and relative amounts). A screening phase followed by a response-surface study allowed optimization of the lipid-mixture composition to obtain the desired Papp value, and definition of a design space where all mixture components combinations fulfilled the desired target at a fixed probability level. The method offers a useful tool for a quick screening in the early stages of drug discovery and/or in preformulation studies, improving efficiency and chance of success in the development of buccal delivery systems. Further studies with other model drugs are planned to confirm the buccal absorption predictive capacity of the developed membrane.

In situ mucoadhesive-thermosensitive liposomal gel as a novel vehicle for nasal extended delivery of opiorphin.

Previous studies proved the effectiveness of an intravenous PEGylated liposomal formulation of opiorphin (1mg/mL) in protecting the drug from enzymatic degradation, and improving intensity and duration of its painkilling effect. Therefore, considering the advantages of nasal administration, the aim of this work was the development of a liposomal mucoadhesive thermo-sensitive in situ gel for the extended nasal delivery of opiorphin. With this purpose, the potential of a series of combinations of different polymers (i.e. chitosan, hydroxypropylmethylcellulose, Poloxamer, Carbopol) in forming solutions able to rapidly gel at the nasal cavity temperature (34 °C) has been investigated. The best formulations were further characterized for gel strength and mucoadhesion properties. The selected formulation, composed by Poloxamer 407 (26.5%) and Carbopol 934P (1%), showed short gelation time at 34 °C (10s) and suitable mucoadhesion duration (5.5h) and strength (27g/cm2). Due to the low volume administrable via the nasal route, a concentrated liposomal formulation of the peptide (16.5mg/mL) was developed and loaded in the selected in situ gel formulation. Ex-vivo permeation studies, by excised nasal porcine mucosa, showed that the liposomal hydrogel formulation enabled a sustained and controlled delivery of opiorphin over more than 5h, and highlighted the role of the liposomal carrier in enhancing up to 6 times permeability coefficient and permeation rate of the peptide through the lipophilic nasal mucosa compared to a free peptide-loaded gel.

Development and Optimization by Quality by Design Strategies of Frovatriptan Orally Disintegrating Tablets for Migraine Management.

BACKGROUND: Frovatriptan is a potent anti-migraine agent with unfavourable slow onset of action, available on the market as film-coated tablets. OBJECTIVE: Optimization, by Quality by Designs strategies, of an orally disintegrating tablet (ODT) formulation of frovatriptan aimed to make its oral administration easier and its dissolution faster than the commercial tablets, thus improving its effectiveness in migraine management. METHOD: A screening D-optimal design was applied to investigate the effects of different levels of kind and amount of ODT special excipient and disintegrant agents (identified as the critical variables) on disintegration time (DT) and % drug dissolved at 30 s (%Diss), selected as the responses to optimize. The best excipients combination, emerged by the screening step, was in-depth investigated by a Response Surface Methodology. RESULTS: A design space was defined where every combination of the selected variables fulfilled the required values for the responses with P ≥ 95%. In particular, the optimized formulation (Pharmaburst® 60% and Na alginate 15%), showed DT = 1.62±0.08 s and %Diss= 9.02±0.47%, with good agreement between measured and calculated values. Moreover, the developed ODT complied with the USP uniformity weight and drug content requirements, exhibited proper hardness and low friability, and provided 100 % dissolved drug within 5 min. CONCLUSION: A frovatriptan ODT formulation was successfully developed by Quality by Design. It represents an effective alternative to conventional tablets, allowing easier oral administration (also to paediatric and geriatric people) and very faster drug dissolution, enhancing patient compliance and facilitating an earlier treatment of migraine attacks.

Development and characterization of fast dissolving tablets of oxaprozin based on hybrid systems of the drug with cyclodextrins and nanoclays.

Previous studies highlighted an increase of the randomly-methylated-ß-cyclodextrin (RAMEB) solubilizing power towards oxaprozin when used in combination with L-arginine (ARG) or sepiolite nanoclay (SV). Therefore, the aim of this work was to investigate the possibility of maximising the RAMEB solubilizing efficacy by a joined approach based on the entrapment in SV of the drug-RAMEB-ARG complex. The quaternary nanocomposite was prepared by different techniques and characterized for solid state and dissolution properties, compared to ternary drug combinations with RAMEB-ARG, RAMEB-SV or ARG-SV. The dissolution rank order was drug-RAMEB-ARG-SV>>drug-RAMEB-ARG≈drug-RAMEB-SV>>drug-ARG-SV. The new hybrid nanocomposite enabled an increase from 60 up to 90% of oxaprozin dissolution parameters compared to the ternary systems with RAMEB-ARG and RAMEB-SV. Moreover, the lowest solubilizing efficacy of ternary systems with ARG-SV evidenced the specific synergic effect of both ARG and SV with RAMEB in enhancing oxaprozin dissolution properties. The superior performance of the quaternary nanocomposite was maintained after incorporation in a tablet formulation. In vivo studies on rats proved that the developed fast-dissolving tablet formulation, containing oxaprozin as cofused system with RAMEB, ARG and SV was more effective than the marketed tablet in terms of faster and more intense pain relieving effect in the treatment of adjuvant-induced arthritis.

Development and in vivo evaluation of an innovative "Hydrochlorothiazide-in Cyclodextrins-in Solid Lipid Nanoparticles" formulation with sustained release and enhanced oral bioavailability for potential hypertension treatment in pediatrics.

An innovative pediatric oral formulation of hydrochlorothiazide (HCT) (2mg/mL), endowed with improved bioavailability and sustained release properties and suitable for the hypertension treatment in pediatric patients, was developed by combining the drug-cyclodextrin complexation and the incorporation of the complex into Solid Lipid Nanoparticles (SLN). Precirol®ATO5-based SLN, with two different surfactants (Pluronic®F68 and Tween®80) loaded with the drug as such or as binary system with hydroxypropyl-beta-cyclodextrin (HPßCd) and sulfobutyl-ether-beta-cyclodextrin (SBEßCd) both as physical mixture (P.M.) or coground product (GR), were prepared using the hot high-shear homogenization followed by ultrasonication method. Loading of the drug:HPßCd both as P.M. and GR gave rise to nanoparticle formation, differently from the HCT:SBEßCd ones, with an entrapment efficiency of about 65%. Such SLN formulations showed an improvement of the drug release rate compared both to the drug suspension and to the free drug-loaded SLN. In all cases the SLN containing the GR systems exhibited better performances than the corresponding with P.M. However, the presence of Tween®80 gave rise to the complete drug release after only 150min, without providing a sustained release, whereas Pluronic®F68-based SLN containing GR were able to assure a sustained release over the time achieving more than 75% drug released at the end of the test, maintaining a constant 1.8-fold increase respect to simple drug suspension. Pluronic®F68-based SLN showed a pharmaceutically acceptable stability up to three months. In vivo studies highlighted the effectiveness of such formulations, enabling a concomitant increased diuretic effect and a sustained drug release and, consequently, enhanced HCT oral bioavailability.

Analysis of physicochemical properties of ternary systems of oxaprozin with randomly methylated-ß-cyclodextrin and l-arginine aimed to improve the drug solubility.

The influence of l-arginine on the complexing and solubilizing power of randomly-methylated-ß-cyclodextrin (RameßCD) towards oxaprozin, a very poorly soluble anti-inflammatory drug, was examined. The interactions between the components were investigated both in solution, by phase-solubility analysis, and in the solid state, by differential scanning calorimetry, FTIR and X-ray powder diffractometry. The morphology of the solid products was examined by Scanning Electron Microscopy. Results of phase-solubility studies indicated that addition of arginine enhanced the RameßCD complexing and solubilizing power of about 3.0 and 4.5 times, respectively, in comparison with the binary complex (both at pH≈6.8). The effect of arginine was not simply additive, but synergistic, being the ternary system solubility higher than the sum of those of the respective drug-CD and drug-arginine binary systems. Solid equimolar ternary systems were prepared by physical mixing, co-grinding, coevaporation and kneading techniques, to explore the effect of the preparation method on the physicochemical properties of the final products. The ternary co-ground product exhibited a dramatic increase in both drug dissolution efficiency and percent dissolved at 60min, whose values (83.6 and 97.1, respectively) were about 3 times higher than the sum of those given by the respective drug-CD and drug-aminoacid binary systems. Therefore, the ternary co-ground system with arginine and RameßCD appears as a very valuable product for the development of new more effective delivery systems of oxaprozin, with improved safety and bioavailability.

Development of cyclodextrin hydrogels for vaginal delivery of dehydroepiandrosterone.

OBJECTIVE: To develop a new vaginal delivery system for a sustained release of dehydroepiandrosterone (DHEA) in the treatment of postmenopausal symptoms, aimed to overcome the problems of poor bioavailability of the drug related to its very low water solubility. METHODS: Cyclodextrin (CD)-containing hydrogels were developed, combining in a single device the hydrogel controlled release and mucoadhesion properties, and the CD solubilizing power towards DHEA. The effect of different CDs, alone or in mixtures, on the hydrogel technological and mucoadhesion characteristics was investigated. The best formulations were loaded with DHEA and characterized for loading efficiency and release properties. KEY FINDINGS: Hydrogels based on HPßCD/γCD (15/10%w/w) or HPßCD/HP γCD (30/20%w/w) combinations proved to be the most effective, giving ovules with the desired mechanical and mucoadhesive properties. Both formulations showed high drug loading efficiency, due to the solubilizing effect of CDs, and provided a sustained in-situ release, with a rate suitably tunable by varying the drug loaded amount and/or the CD combination. CONCLUSIONS: The proposed formulative strategy allowed to develop an intravaginal device with right consistency and elasticity, easy to apply, able to be retained in situ over 8 h, and to provide an effective DHEA loading and a tunable release rate.