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.

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.

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.

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.

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.

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.

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.

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 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.

Development of enteric-coated calcium pectinate microspheres intended for colonic drug delivery.

Enteric-coated calcium pectinate microspheres (MS) aimed for colon drug delivery have been developed, by using theophylline as a model drug. The influence of pectin type (amidated or non-amidated) and MS preparation conditions (CaCl2 concentration and cross-linking time) was investigated upon the drug entrapment efficiency and its release behaviour. Drug stability and drug-polymer interactions were studied by Differential Scanning Calorimetry, thermogravimetry, X-ray diffractometry and FTIR spectroscopy. Enteric coating with Eudragit S100 enabled maintenance of MS integrity until its expected arrival to colon. The coating was also useful to improve the stability of MS during storage, avoiding morphologic changes observed for uncoated MS stored under ambient conditions. Entrapment efficiency increased by reducing cross-linking time, and (only in the case of non-amidated pectin) by increasing CaCl2 concentration. On the other hand, release tests performed simulating the gastro-intestinal pH variation evidenced an inverse relationship between CaCl2 concentration and drug release rate, whereas no influence of both pectin type and cross-linking time was found. Unexpectedly, addition of pectinolytic enzymes to the colonic medium did not give rise to selective enzymatic degradation of MS. Notwithstanding this unforeseen result, coated MS prepared at 2.5% w/v CaCl2 concentration were able to adequately modulate drug release through a mixed approach of pH and transit time control, avoiding drug release in the gastric ambient, and reaching the colonic targeting where 100% release was achieved within less than 24h.

Sustained-release matrix tablets of metformin hydrochloride in combination with triacetyl-beta-cyclodextrin.

The low bioavailability and short half-life of metformin hydrochloride (MH) make the development of sustained-release forms desirable. However, drug absorption is limited to the upper gastrointestinal (GI) tract, thus requiring suitable delivery systems providing complete release during stomach-to-jejunum transit. This study was undertaken to develop a MH sustained-release formulation in compliance with these requirements. The strategy proposed is based on direct-compressed matrix tablets consisting of a combination of MH with the hydrophobic triacetyl-beta-cyclodextrin (TAbetaCD), dispersed in a polymeric material. Different polymers were tested as excipients, i.e. hydroxypropylmethylcellulose, xanthan gum, chitosan, ethylcellulose, Eudragit L100-55, and Precirol. Compatibility among the formulation components was assessed by DSC analysis. All the tablets were examined for drug release pattern in simulated gastric and jejunal fluids used in sequence to mimic the GI transit. Release studies demonstrated that blends of a hydrophobic swelling polymer (hydroxypropylmethylcellulose or chitosan) with a pH-dependent one (Eudragit L100-55) were more useful than single polymers in controlling drug release. Moreover, the main role played by the MH-TAbetaCD system preparation method (i.e. grinding or spray-drying) in determining the behaviour of the final formulation was evidenced. In fact, for a given matrix-tablet composition, different sustained-release effects were obtained by varying the relative amounts of MH-TAbetaCD as ground or spray-dried product. In particular, the 1:1 (w/w) blend of such systems, dispersed in a Eudragit-chitosan polymeric matrix, fully achieved the prefixed goal, giving about 30% released drug after 2h at gastric pH, and overcoming 90% released drug within the subsequent 3h in jejunal fluid.

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.