Comparison of liposomal and NLC (nanostructured lipid carrier) formulations for improving the transdermal delivery of oxaprozin: Effect of cyclodextrin complexation.

The combined strategy of drug-cyclodextrin (CD) complexation and complex loading into nanocarriers (deformable liposomes or nanostructured lipid carriers (NLC)), was exploited to develop effective topical formulations for oxaprozin transdermal administration. Oxaprozin was loaded as ternary complex with randomly-methylated-ßCD and arginine, selected as the best system in improving drug solubility. The colloidal dispersions, characterized for particle size, zeta-potential and entrapment efficiency, were investigated for drug permeation properties in comparison with a plain drug aqueous suspension, a ternary complex aqueous solution and a plain drug liposomal or NLC dispersion. Experiments with artificial membranes showed that the joined use of CD and both liposomes or NLC enabled a marked increase of the drug permeability (16 and 8 times, respectively) and was significantly more effective (P<0.05) than the drug as ternary complex (3.2 times increase), and the corresponding liposomal or NLC dispersion of plain drug (5.6 and 4.3 times increase, respectively). Experiments with excised human skin confirmed the significantly (P<0.05) better performance of deformable liposomes than NLC in promoting drug permeation; moreover, they evidenced a more marked permeability increase compared to the plain drug (24 and 12 fold, respectively), attributed to a possible enhancer effect of the nanocarriers components and/or of the randomly-methylated-ßCD.

Quality of wound dressings: a first step in establishing shared criteria and objective procedures to evaluate their performance.

OBJECTIVE: There are no well-defined criteria for assessing the efficacy and quality of wound dressings, and evaluation is often simplistic and based on the subjective opinion of the health-care professional. The aim of this study was to identify specific parameters suitable for measuring dressings' performance, and to recommend laboratory tests able to evaluate these specific criteria in an objective manner. METHOD: After reviewing all tests currently used in Italy and examining the criteria for evaluating the quality of dressings, the authors selected 12 clinically significant parameters. These parameters were measured using standard and non-standard tests, and in some cases, these tests were modified and improved to simulate real-life conditions more accurately. RESULTS: Most of the tests used were able to discriminate well between dressings belonging to different brands, with some tests being more suitable than others for the assessment of specific dressings. CONCLUSION: These results highlighted some issues in the standard testing procedures, such as the need of a suitable fluid that mimics the real exudate, and the importance of standard temperature and humidity conditions during testing. Our study paves the way for a larger project aimed at a systematic evaluation of dressing quality able to assess every wound dressing on the market.

Polymeric mucoadhesive tablets for topical or systemic buccal delivery of clonazepam: Effect of cyclodextrin complexation.

Two kinds of mucoadhesive buccal tablets of clonazepam (CLZ) were developed to provide, a prolonged local or systemic delivery respectively. Tablets prepared by direct compression of combinations of different polymers were tested for swelling, erosion and residence time properties. Carbopol 971P/hydroxypropylmethylcellulose and Poloxamer/chitosan mixtures were the best and were selected for drug loading. The effect of CLZ complexation with different cyclodextrins was investigated. Randomly-methylated-ßCD (RAMEßCD) was the most effective, allowing 100% drug released increase from local-delivery buccal tablets. Kollicoat was the best among the tested backing-layers, assuring a unidirectional release from systemic-delivery buccal tablets (<0.8% drug released in simulated saliva after 24h). In vitro permeation studies from coated-tablets showed that CLZ loading as RAMEßCD-coground enabled a 5-times increase in drug flux and permeability. Therefore, complexation with RAMEßCD was a successful strategy to improve the CLZ performance from buccal tablets for both local or systemic action.

Combined use of bile acids and aminoacids to improve permeation properties of acyclovir.

The aim of this work was to develop a topical formulation with improved permeation properties of acyclovir. Ursodeoxycholic (UDC) and dehydrocholic (DHC) acids were tested as potential enhancers, alone or in combination with different aminoacids. Equimolar binary and ternary systems of acyclovir with cholic acids and basic, hydrophilic or hydrophobic aminoacids were prepared by co-grinding in a high vibrational micromill. Differential scanning calorimetry (DSC) was used to characterize the solid state of these systems, while their permeation properties were evaluated in vitro through a lipophilic artificial membrane. UDC was more than 2 times more effective than DHC in improving drug AUC and permeation rate. As for the ternary systems drug-UDC-aminoacid, only the combined use of l-lysine with UDC acid produced an evident synergistic effect in enhancing drug permeation properties, enabling an almost 3 and 8 times AUC increase compared to the binary UDC system or the pure drug, respectively. The best systems were selected for the development of topical cream formulations, adequately characterized and tested for in vitro drug permeation properties and stability on storage. The better performance revealed by acyclovir-UDC-l-lysine was mainly attributed to the formation of a more permeable activated system induced by the multicomponent co-grinding process.

Development and characterization of functionalized niosomes for brain targeting of dynorphin-B.

A niosomal formulation, functionalized with N-palmitoylglucosamine, was developed as potential brain targeted delivery system of dynorphin-B. In fact, this endogenous neuropeptide, selective agonist of k opioid receptors, is endowed with relevant pharmacological activities on the central nervous system, including a marked antinociceptive effect, but is unable to cross the blood brain barrier (BBB), thus requiring intracerebroventricular administration. Statistical design of experiments was utilized for a systematic evaluation of the influence of variations of the relative amounts of the components of the vesicle membrane (Span 60, cholesterol and SolulanC24) on vesicle mean diameter, polydispersity index and drug entrapment efficiency, chosen as the responses to optimize. A Scheffé simplex-centroid design was used to obtain the coefficients of the postulated mathematical model. The study of the response surface plots revealed that variations of the considered factors had different effects on the selected responses. The desirability function enabled for finding the optimal mixture composition, which represented the best compromise to simultaneously optimize all the three responses. The experimental values obtained with the optimized formulation were very similar to the predicted ones, proving the validity of the proposed regression model. The optimized niosomal formulation of dynorphin-B administered intravenously to mice (100mg/kg) showed a pronounced antinociceptive effect, significantly higher (P<0.05) than that given by i.v. administration of the simple solution of the peptide at the same concentration, proving its effectiveness in enabling the peptide brain delivery. These positive results suggest that the proposed approach could be successfully extended to other neuro-active peptides exerting a strong central action, even at low doses, but unable to cross the BBB.

Quality by design approach for developing chitosan-Ca-alginate microspheres for colon delivery of celecoxib-hydroxypropyl-ß-cyclodextrin-PVP complex.

The aim of the present work was to develop a new multiparticulate system, designed for colon-specific delivery of celecoxib for both systemic (in chronotherapic treatment of arthritis) and local (in prophylaxis of colon carcinogenesis) therapy. The system simultaneously benefits from ternary complexation with hydroxypropyl-ß-cyclodextrin and PVP (polyvinylpyrrolidone), to increase drug solubility, and vectorization in chitosan-Ca-alginate microspheres, to exploit the colon-specific carrier properties of these polymers. Statistical experimental design was employed to investigate the combined effect of four formulation variables, i.e., % of alginate, CaCl2, and chitosan and time of cross-linking on microsphere entrapment efficiency (EE%) and drug amount released after 4h in colonic medium, considered as the responses to be optimized. Design of experiment was used in the context of Quality by Design, which requires a multivariate approach for understanding the multifactorial relationships among formulation parameters. Doehlert design allowed for defining a design space, which revealed that variations of the considered factors had in most cases an opposite influence on the responses. Desirability function was used to attain simultaneous optimization of both responses. The desired goals were achieved for both systemic and local use of celecoxib. Experimental values obtained from the optimized formulations were in both cases very close to the predicted values, thus confirming the validity of the generated mathematical model. These results demonstrated the effectiveness of the proposed jointed use of drug cyclodextrin complexation and chitosan-Ca-alginate microsphere vectorization, as well as the usefulness of the multivariate approach for the preparation of colon-targeted celecoxib microspheres with optimized properties.

Development of a new delivery system consisting in "drug--in cyclodextrin--in nanostructured lipid carriers" for ketoprofen topical delivery.

A new delivery system based on drug cyclodextrin (Cd) complexation and loading into nanostructured lipid carriers (NLC) has been developed to improve ketoprofen therapeutic efficacy. The proposed strategy exploits both the solubilizing and stabilizing properties of Cds and the prolonged release, high tolerability and percutaneous absorption enhancer properties of NLC. Two different polymeric Cds, i.e. ß-Cd-epichlorohydrin polymer (EPI-ßCd) and carboxymethylathed-ß-Cd-epichlorohydrin polymer (EPI-CMßCd) were tested and two different techniques to obtain solid ketoprofen-polymeric Cd complexes (i.e. co-grinding and co-lyophilization) were compared, to investigate the influence of the preparation method on the physicochemical properties of the end product. EPI-ßCd was more effective than EPI-CMßCd in enhancing the solubility and dissolution properties of ketoprofen. Co-grinding in dry conditions was the best preparation technique of solid drug-Cd systems, allowing obtainment of homogeneous amorphous particles of nanometric range. NLC consisting in a mixture of Compritol® 888 ATO (glyceryl behenate) and Labrafac Lipophile were obtained by ultrasonication. Both empty and loaded NLC were suitably characterized for particle size, pH, entrapment efficiency and drug release behavior. The best (drug-Cd)-loaded NLC system, formulated into a xanthan hydrogel, exhibited drug permeation properties clearly better than those of the plain drug suspension or the plain drug-loaded NLC, in virtue of the simultaneous exploitation of the solubilizing effect of cyclodextrin and the penetration enhancer properties of NLC.

Influence of cross-linking agent type and chitosan content on the performance of pectinate-chitosan beads aimed for colon-specific drug delivery.

Pectinate-chitosan-beads aimed for colon theophylline delivery have been developed. The effect of zinc or calcium ions as cross-linking agent, and of chitosan concentration on the properties and colon-targeting performance of beads was investigated. Beads were characterized for morphology, entrapment efficiency and mucoadhesion properties. Zn-pectinate-chitosan beads formed a stronger gel network than the Ca-containing ones, enabling a greater entrapment efficiency, which further increased with chitosan content, probably due to polyelectrolyte complexes formation. Transport studies across Caco-2 cells evidenced a significant (p > 0.05) drug permeation increase from all beads with respect to drug alone, attributable to the enhancer and/or mucoadhesion properties of the polymers, and Ca-pectinate-chitosan beads were more effective than the Zn-containing ones. Beads formulated as enteric-coated tablets demonstrated good colon-targeting properties, and no differences were observed in drug-release profiles from Zn- or Ca-pectinate-chitosan beads. Therefore, Ca-pectinate-chitosan beads emerged as the choice formulation, joining colon-targeting specificity with better permeation enhancer power.

Improvement of oxaprozin solubility and permeability by the combined use of cyclodextrin, chitosan, and bile components.

The effect of the combined use of randomly methylated ß-cyclodextrin (RAMEB), chitosan (CS), and bile components (dehydrocholic (DHCA) or ursodeoxycholic (UDCA) acids and their sodium salts) on solubility and permeability through Caco-2 cells of oxaprozin (a very poorly water-soluble non-steroidal anti-inflammatory drug) has been investigated. Addition of CS, bile acids, and their sodium salts increased the RAMEB solubilizing power of 4, 2, and 5 times, respectively. Drug-RAMEB-CS co-ground systems showed very higher dissolution rate than corresponding drug-RAMEB systems. Addition of bile components further improved drug dissolution rate. The CS presence enabled a significant increase in drug permeability through Caco-2 cells with respect to drug-RAMEB systems. Moreover, CS and NaDHC showed a synergistic enhancer effect, enabling a 1.4-fold permeability increase in comparison with systems without bile salt. However, unexpectedly, no significant differences were found between physical mixtures and co-ground products, indicating that drug permeation improvement was due to the intrinsic enhancer effect of the carriers and not to drug-carrier interactions brought about by co-grinding, as instead found in dissolution rate studies. The combined use of RAMEB, CS, and NaDHC could be exploited to develop effective oral dosage forms of oxaprozin, with increased drug solubility and permeability, and then improved bioavailability.

Mixture experiment methods in the development and optimization of microemulsion formulations.

Microemulsion formulations represent an interesting delivery vehicle for lipophilic drugs, allowing for improving their solubility and dissolution properties. This work developed effective microemulsion formulations using glyburide (a very poorly-water-soluble hypoglycaemic agent) as a model drug. First, the area of stable microemulsion (ME) formations was identified using a new approach based on mixture experiment methods. A 13-run mixture design was carried out in an experimental region defined by constraints on three components: aqueous, oil and surfactant/cosurfactant. The transmittance percentage (at 550 nm) of ME formulations (indicative of their transparency and thus of their stability) was chosen as the response variable. The results obtained using the mixture experiment approach corresponded well with those obtained using the traditional approach based on pseudo-ternary phase diagrams. However, the mixture experiment approach required far less experimental effort than the traditional approach. A subsequent 13-run mixture experiment, in the region of stable MEs, was then performed to identify the optimal formulation (i.e., having the best glyburide dissolution properties). Percent drug dissolved and dissolution efficiency were selected as the responses to be maximized. The ME formulation optimized via the mixture experiment approach consisted of 78% surfactant/cosurfacant (a mixture of Tween 20 and Transcutol, 1:1, v/v), 5% oil (Labrafac Hydro) and 17% aqueous phase (water). The stable region of MEs was identified using mixture experiment methods for the first time.

Response surface methodology in the optimization of chitosan-Ca pectinate bead formulations.

This study describes the application of a multi-varied experimental design methodology to the optimization of a bead formulation based on a mixed network of Ca pectinate and chitosan. The effect of varying the relative percent of the three components used for the bead production, i.e. pectin, chitosan and CaCl(2), has been systematically investigated with the aim of identifying their best levels to optimize drug encapsulation efficiency (considered as the experimental response to be maximized), as well as to highlight possible interactions among the components. The study was applied to two different drugs, i.e. prednisone and theophylline, selected, respectively, as model insoluble and relatively soluble drugs, in order to evaluate the influence of this parameter as well. Different bead batches were prepared according to Doehlert and D-optimal design and randomly evaluated for drug encapsulation efficiency. Analysis of response surface plots allowed identification of the best combination of the three bead components in order to maximize drug encapsulation efficiency. The most effective compositions were chitosan 3% (w/v), pectin 9% (w/v), CaCl(2) 4% (w/v) for the theophylline-loaded beads and chitosan 0.75% (w/v), pectin 6% (w/v), CaCl(2) 7.9% (w/v) for the prednisone-loaded ones. The good correspondence between calculated and experimental values indicated in both cases the validity of the generated statistical models for the prediction of microsphere encapsulation efficiency. The different results obtained for the two drugs indicated the importance of the greater or lesser drug lipophilicity in determining the optimal bead composition with the highest encapsulation efficiency.

Microspheres for colonic delivery of ketoprofen-hydroxypropyl-beta-cyclodextrin complex.

A new multiparticulate system, with the potential for site-specific delivery to the colon, has been developed using ketoprofen as model drug. The system simultaneously exploits cyclodextrin complexation, to improve drug solubility, and vectorization in microspheres (MS) based on Ca-pectinate and chitosan. The effect of complexation with hydroxypropyl-beta-cyclodextrin (HPbetaCyd) and of chitosan presence on drug entrapment efficiency and release properties, as well on the drug permeation rate across Caco-2 cells has been investigated. Solid-state interactions between the components have been investigated by FTIR spectroscopy, differential scanning calorimetry and X-ray powder diffractometry. The morphology of MS was examined by scanning electron microscopy. Release studies revealed a different behaviour for MS containing drug alone or as complex: drug alone was released faster than in the presence of cyclodextrin from MS without chitosan, due to a reservoir effect. The opposite was found for MS containing chitosan, due to a competition effect between polymer and drug for the cyclodextrin. Cytotoxicity tests demonstrated the safety of these formulations. Permeation studies showed an increased permeation of the drug formulated as MS, particularly marked when it was used as complex, thus revealing an enhancing power of both cyclodextrin and chitosan with a synergistic effect in improving drug permeation.