Deformable Vesicles with Edge Activators for the Transdermal Delivery of Non-Psychoactive Cannabinoids.

BACKGROUND: Transdermal delivery of highly lipophilic molecules is challenging due to the strong barrier function of the skin. Vesicles with penetration enhancers are safe and efficient systems that could improve the transdermal delivery of non-psychoactive cannabinoids such as cannabidiol and desoxy-cannabidiol. In the last decades, research interest in desoxy-cannabidiol as a potent drug with anti-nociceptive properties has risen. Still, its scarce market availability poses a limit for both research and clinical applications. Therefore, it is necessary to improve the synthesis to produce sufficient amounts of desoxy-cannabidiol. Moreover, also the formulation aspects for this drug are challenging and require to be addressed to meet an efficient delivery to the patients. OBJECTIVE: This work aimed to develop innovative phospholipid-based vesicles with propylene glycol (PG), oleic acid (OA), or limonene as edge activators, for the transdermal delivery of highly lipophilic drugs such as non-psychoactive cannabinoids. In particular, desoxy-cannabidiol was selected thanks to its anti-nociceptive activity, and its synthesis was improved enhancing the stereoselectivity of its synthon's production. METHODS: Desoxy-cannabidiol was synthesized by Lewis acid-mediated condensation of p-mentha-2,8-dien- 1-ol and m-pentylphenol, improving the stereoselectivity of the first synthon's production. Transethosomes containing 20-50% w/w PG, 0.4-0.8% w/w OA, or 0.1-1% w/w limonene were optimized and loaded with cannabidiol or desoxy-cannabidiol (0.07-0.8% w/w, 0.6-7.0 mg/mL). Ex-vivo studies were performed to assess both the skin permeation and accumulation of the cannabinoids, as well as the penetration depth of fluorescein- loaded systems used as models. RESULTS: An enantioselective bromination was added to the pathway, thus raising the production yield of pmentha- 2,8-dien-1-ol to 81% against 35%, and the overall yield of desoxy-cannabidiol synthesis from 12% to 48%. Optimized transethosomes containing 0.6 mg/mL cannabinoids were prepared with 1:10 PG:lipid weight ratio, 0.54 OA:lipid molar ratio, and 0.3 limonene:lipid molar ratio, showing good nanometric size (208 ± 20.8 nm - 321 ± 26.3 nm) and entrapment efficiency (> 80%). Ex-vivo tests showed both improved skin permeation rates of cannabinoids (up to 21.32 ± 4.27 µg/cm2 cannabidiol), and skin penetration (depth of fluorescein up to 240 µm, with PG). CONCLUSION: Desoxy-cannabidiol was successfully produced at high yields, and formulated into transethosomes optimized for transdermal delivery. Loaded vesicles showed improved skin penetration of desoxy-cannabidiol, cannabidiol and a lipophilic probe. These results suggest the potential of these carriers for the transdermal delivery of highly lipophilic drugs.

Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening.

A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects. Among the synthesized compounds, the 4-phenylderivative 12 and the 6-phenylderivative 25 exerted a promising F508del CFTR rescue ability. On these compounds, preliminary in vivo pharmacokinetic (PK) studies were carried out, evidencing a favorable PK profile per se or after incorporation into lipid formulations. Therefore, the selected compounds are good candidates for future extensive investigation to evaluate and develop novel CFTR correctors based on the angelicin structure.

Self-Emulsifying Formulations to Increase the Oral Bioavailability of 4,6,4'-Trimethylangelicin as a Possible Treatment for Cystic Fibrosis.

4,6,4'-trimethylangelicin (TMA) is a promising pharmacological option for the treatment of cystic fibrosis (CF) due to its triple-acting behavior toward the function of the CF transmembrane conductance regulator. It is a poorly water-soluble drug, and thus it is a candidate for developing a self-emulsifying formulation (SEDDS). This study aimed to develop a SEDDS to improve the oral bioavailability of TMA. Excipients were selected on the basis of solubility studies. Polyoxyl-35 castor oil (Cremophor® EL) was proposed as surfactant, diethylene glycol-monoethyl ether (Transcutol® HP) as cosolvent, and a mixture of long-chainmono-,di-, and triglycerides (Maisine® CC) or medium-chain triglycerides (LabrafacTM lipophile) as oil phases. Different mixtures were prepared and characterized by measuring the emulsification time, drop size, and polydispersity index to identify the most promising formulation. Two formulations containing 50% surfactant (w/w), 40% cosolvent (w/w), and 10% oil (w/w) (Maisine® CC or LabrafacTM lipophile) were selected. The results showed that both formulations were able to self-emulsify, producing nanoemulsions with a drop size range of 20-25 nm, and in vivo pharmacokinetic studies demonstrated that they were able to significantly increase the oral bioavailability of TMA. In conclusion, SEEDS are useful tools to ameliorate the pharmacokinetic profile of TMA and could represent a strategy to improve the therapeutic management of CF.

Exploring mechanochemical parameters using a DoE approach: Crystal structure solution from synchrotron XRPD and characterization of a new praziquantel polymorph.

A rotated Doehlert matrix was utilized to explore the experimental design space around the milling parameters of Praziquantel (PZQ) polymorph B formation in terms of frequency and milling time. Three experimental responses were evaluated on the resulting ground samples: two quantitative responses, i.e. median particle size by Laser Light scattering (LLS) and drug recovery by HPLC, and one qualitative dependent variable, i.e. the obtained PZQ crystalline form, characterized through X-Ray Powder Diffraction (XRPD) and confirmed by Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). Temperature inside the jars was kept under constant control during the milling process by using temperature sensor equipped jars (thermojars), thus allowing evaluation of the obtained solid states at each experimental point, considering the specific temperature of the process. This explorative analysis led to the finding of a novel PZQ polymorph, named "Form C", produced without degradation, then fully characterized, including by means of Synchrotron XRPD, Polarimetric, FT-IR, SS-NMR, ESEM and saturation solubility. Crystal structure was solved from XRPD data and its geometry was optimized by DFT calculations (CASTEP). Finally, Form C and Form A activity against adult schistosoma mansoni were compared through in vitro testing, and Form C's physical stability checked. The new polymorph, crystallizing in space group I2/c, physically stable for approximately 2 months, showed a m.p. of 106.84 °C and displayed excellent biopharmaceutical properties (water solubility of 382.69±9.26 mg/l), while preserving excellent activity levels against adult schistosoma mansoni.

Combining Mechanochemistry and Spray Congealing for New Praziquantel Pediatric Formulations in Schistosomiasis Treatment.

Praziquantel (PZQ) is the first line drug for the treatment of schistosome infections and is included in the WHO Model List of Essential Medicines for Children. In this study, the association of mechanochemical activation (MA) and the spray congealing (SC) technology was evaluated for developing a child-friendly PZQ dosage form, with better product handling and biopharmaceutical properties, compared to MA materials. A 1:1 by wt PZQ-Povidone coground-was prepared in a vibrational mill under cryogenic conditions, for favoring amorphization. PZQ was neat ground to obtain its polymorphic form (Form B), which has an improved solubility and bioactivity. Then, activated PZQ powders were loaded into microparticles (MPs) by the SC technology, using the self-emulsifying agent Gelucire® 50/13 as a carrier. Both, the activated powders and the corresponding loaded MPs were characterized for morphology, wettability, solubility, dissolution behavior, drug content, and drug solid state (Hot Stage Microscopy (HSM), Differential Scanning Calorimetry (DSC), X-Ray Powder Diffraction Studies (PXRD), and FT-IR). Samples were also in vitro tested for a comparison with PZQ against Schistosoma mansoni newly transformed schistosomula (NTS) and adults. MPs containing both MA systems showed a further increase of biopharmaceutical properties, compared to the milled powders, while maintaining PZQ bioactivity. MPs containing PZQ Form B represented the most promising product for designing a new PZQ formulation.

Impact of Different Dry and Wet Granulation Techniques on Granule and Tablet Properties: A Comparative Study.

Four granulation techniques were compared evaluating their impact on granule properties and the tablet tensile strength. A common formulation was chosen to be processed with both wet and dry granulation techniques: roll compaction/dry granulation, high-shear granulation, twin-screw granulation, and fluidized-bed granulation. The produced granules were characterized in terms of granule size distribution, X-ray powder diffraction, scanning electron microscopy, porosity, and strength. Granules were tableted, and the tablets were evaluated in terms of tensile strength and mass variation. A particular focus was given to granule strength measurements. Granule strength showed to be strongly affected by the used granulation technique. Moreover, a nonlinear inverse correlation was identified between granule strength and tablet tensile strength. High-shear granulation produced the densest and strongest granules, which presented the lowest tablet tensile strength. Granules manufactured by roll compaction/dry granulation showed no loss in tabletability with the used formulation even for the more compacted and strong granules. Tablets produced by the fluidized-bed granulation showed the best properties in terms of tensile strength and mass variation. However, twin-screw granulation presented comparable results for the specific formulation evaluated in the study, thus revealing a great potential of this technique.

Sublingual Administration of Sildenafil Oro-dispersible Film: New Profiles of Drug Tolerability and Pharmacokinetics for PDE5 Inhibitors.

Objective: Type 5 phosphodiesterase inhibitors (PDE5i) are efficient drugs used for treatment of erectile dysfunction (ED); however, a large discontinuation rate due to major side effects is reported. The aim of this study was to evaluate the possible improvement of sildenafil (Sild) pharmacokinetics associated to the sublingual administration of the new available oro-dispersible film (ODF), compared to both the oro-dispersible tablet (ODT) and the film-coated tablet (FCT) as original per os formulation. Methods:In vitro disaggregation test, dissolution test, and permeation test in specific devices to estimate the trans-mucosal absorption. In vivo analysis of serum Sild levels, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), was performed in 20 patients with psychogenic ED receiving alternatively per os FCT or sublingual ODT or ODF, at an equal dosage (50 mg). Pharmacokinetic parameters of Sild and adverse drug reactions experienced after the dosing of each formulation were compared. Results:In vitro, ODF showed the highest time to disaggregation and an increased rate of permeation compared to both ODT and FCT (P = 0.017 and P = 0.008, respectively). In vivo, compared to both FCT and ODT, ODF showed a faster increase of serum Sild levels (serum levels at 15 min from dosing, respectively: 2.24 ± 1.4 ng/ml FCT, 0.5 ± 0.3 ng/ml ODT, and 13.5 ± 9.1 ng/ml ODF; P < 0.01 and P < 0.05 vs. ODF) together with a higher drug bioavailability within 60 min from dosing (relative AUC60min vs. FCT, respectively: 100.0 ± 44.9% FCT, 183.8 ± 75.4% ODT, and 304.2 ± 156.0% ODF). A trend toward lower peak serum levels was observed for ODF. Finally, ODF showed a lower prevalence of headache compared to FCT (1 vs. 35%; P < 0.05) and improved pattern of flushing and nasal congestion. Conclusion: Sublingual Sild ODF improves the drug tolerability through a likely modified pharmacokinetic, suggesting a possible implication also in the clinical efficacy profile. Sublingual administration of oro-dispersible formulations may represent a strategy to ameliorate the adherence to therapy with PDE5i, particularly in patients discouraged by side effects.

Experimental Determination of Drug Diffusion Coefficients in Unstirred Aqueous Environments by Temporally Resolved Concentration Measurements.

The diffusion coefficient (also known as diffusivity) of an active pharmaceutical ingredient (API) is a fundamental physicochemical parameter that affects passive diffusion through biological barriers and, as a consequence, bioavailability and biodistribution. However, this parameter is often neglected, and it is quite difficult to find diffusion coefficients of small molecules of pharmaceutical relevance in the literature. The available methods to measure diffusion coefficients of drugs all suffer from limitations that range from poor sensitivity to high selectivity of the measurements or the need for dedicated instrumentation. In this work, a simple but reliable method based on time-resolved concentration measurements by UV-visible spectroscopy in an unstirred aqueous environment was developed. This method is based on spectroscopic measurement of the variation of the local concentration of a substance during spontaneous migration of molecules, followed by standard mathematical treatment of the data in order to solve Fick's law of diffusion. This method is extremely sensitive and results in highly reproducible data. The technique was also employed to verify the influence of the environmental characteristics (i.e., ionic strength and presence of complexing agents) on the diffusivity. The method can be employed in any research laboratory equipped with a standard UV-visible spectrophotometer and could become a useful and straightforward tool in order to characterize diffusion coefficients in physiological conditions and help to better understand the drug permeability process.

Bioaccumulation and effects of titanium dioxide nanoparticles and bulk in the clam Ruditapes philippinarum.

Biochemical and cellular responses to low concentrations of TiO2 nanoparticles (nTiO2, 1 and 10 µg/L) and bulk (bTiO2, 10 µg/L) were evaluated in gills, digestive gland and haemolymph of the clam Ruditapes philippinarum after1, 3 and 7 days' exposure. At 7 days, titanium content was determined in gills and digestive gland. nTiO2 significantly increased antioxidant enzyme activities in both tissues, and lipid peroxidation in digestive gland at 10 µg/L only, and affected glutathione S-transferase activity. Slighter variations were observed in bTiO2-treated clams. A significant Ti bioaccumulation was detected in both gills and digestive gland of 10 µg nTiO2/L-exposed clams. In haemolymph, nTiO2 affected total haemocyte count, haemocyte proliferation, haemocyte diameter and volume, and induced DNA damage. Overall, this study demonstrated that TiO2 alters most of the biomarkers measured in clams, although responses were differently modulated depending on tissues and exposure conditions, and indicated that nTiO2 can be accumulated by bivalves, suggesting a potential risk for filter-feeding animals.

In vivo exposure of the marine clam Ruditapes philippinarum to zinc oxide nanoparticles: responses in gills, digestive gland and haemolymph.

Potential nanoparticle (NP) toxicity poses a growing concern in marine coastal environments. Among NPs, zinc oxide nanoparticles (nZnO) are widely used in many common products that ultimately become deposited in coastal habitats from multiple non-point sources. In this study, we evaluated the in vivo effects of nZnO in the clam Ruditapes philippinarum. Animals were exposed to nZnO (1 and 10 µg/L) and ZnCl2 (10 µg/L) for 7 days. ZnCl2 was used to compare the effects of the NPs to those of Zn(2+) and to ascertain whether nZnO toxicity is attributable to the release of ions into the aquatic medium. At differing time intervals during the exposure, several biochemical and cellular responses were evaluated in the clam gills, digestive gland, and haemolymph. The results showed that nZnO, at concentrations close to the predicted environmental levels, significantly affected various parameters in clam tissues. Significant increases in catalase and superoxide dismutase activities and a decreasing trend of glutathione S-transferase activity indicated the involvement of oxidative stress in nZnO toxicity. In clams exposed to ZnCl2, slight variations in antioxidant enzyme activities were detected with respect to nZnO-treated clams. However, no damage to lipids, proteins or DNA was revealed in all exposure conditions, suggesting a protection of antioxidant enzymes in the tissues. Of the various haemolymph parameters measured, haemocyte proliferation increased significantly, in ZnCl2-treated clams in particular. Under nZnO (10 µg/L) and ZnCl2 exposure, DNA damage in haemocytes was also revealed, but it was lower in clams exposed to ZnCl2. A decreasing trend in gill AChE activity of treated clams proposed a possible role of zinc ions in nZnO toxicity. However, the dissimilar modulation of the responses in the nZnO- and ZnCl2-exposed clams suggested different mechanisms of action, with nZnO toxicity possibly depending not only on the release of zinc ions but also on NP-specific features. Changes in the biological parameters measured in the clams were consistent with Zn accumulation in their gills and digestive glands.

Texture analysis as a tool to study the kinetics of wet agglomeration processes.

In this work wet granulation experiments were carried out in a planetary mixer with the aim to develop a novel analytical tool based on surface texture analysis. The evolution of a simple formulation (300g of microcrystalline cellulose with a solid binders pre-dispersed in water) was monitored from the very beginning up to the end point and information on the kinetics of granulation as well as on the effect of liquid binder amount were collected. Agreement between texture analysis and granules particle size distribution obtained by sieving analysis was always found. The method proved to be robust enough to easily monitor the process and its use for more refined analyses on the different rate processes occurring during granulation is also suggested.

In vitro exposure of haemocytes of the clam Ruditapes philippinarum to titanium dioxide (TiO2) nanoparticles: nanoparticle characterisation, effects on phagocytic activity and internalisation of nanoparticles into haemocytes.

The continuous growth of nanotechnology and nano-industries, the considerable increase of products containing nanoparticles (NPs) and the potential release of NPs in aquatic environments suggest a need to study NP effects on aquatic organisms. In this context, in vitro assays are commonly used for evaluating or predicting the negative effects of chemicals and for understanding their mechanisms of action. In this study, a physico-chemical characterisation of titanium dioxide NPs (n-TiO2) was performed, and an in vitro approach was used to investigate the effects of n-TiO2 on haemocytes of the clam Ruditapes philippinarum. In particular, the effects on haemocyte phagocytic activity were evaluated in two different experiments (with and without pre-treatment of haemocytes) by exposing cells to P25 n-TiO2 (0, 1 and 10 µg/mL). In addition, the capability of n-TiO2 to interact with clam haemocytes was evaluated with a transmission electron microscope (TEM). In this study, n-TiO2 particles showed a mean diameter of approximately 21 nm, and both anatase (70%) and rutile (30%) phases were revealed. In both experiments, n-TiO2 significantly decreased the phagocytic index compared with the control, suggesting that NPs are able to interfere with cell functions. The results of the TEM analysis support this hypothesis. Indeed, we observed that TiO2 NPs interact with cell membranes and enter haemocyte cytoplasm and vacuoles after 60 min of exposure. To the best of our knowledge, this is the first study demonstrating the internalisation of TiO2 NPs into R. philippinarum haemocytes. The present study can contribute to the understanding of the mechanisms of action of TiO2 NPs in bivalve molluscs, at least at the haemocyte level.

Role of proton pump inhibitor on esophageal carcinogenesis and pancreatic acinar cell metaplasia development: an experimental in vivo study.

Chronic gastro-duodenal reflux in the esophagus is a major risk for intestinal metaplasia and Barrett's adenocarcinoma. A role for chronic use of proton pump inhibitor (PPI) in the increased incidence of esophageal adenocarcinoma in Western countries has been previously suggested. The aim of this work was to study the effect of chronic administration of omeprazole (a proton pump inhibitor) per os in a model of reflux induced esophageal carcinogenesis. One week after esophago-gastro-jejunostomy, 115 Sprague-Dawley rats were randomized to receive 10 mg/Kg per day of omeprazole or placebo, 5 days per week. The esophago-gastric specimens were collected 28 ± 2 weeks after randomization and analyzed in a blinded fashion. Mortality and esophageal metaplasia rates did not differ between the two groups (p = 0.99 for mortality, p = 0.36 for intestinal metaplasia and p = 0.66 for multi-layered epithelium). Gastric pancreatic acinar cell metaplasia (PACM) was more frequently observed in PPI-treated rats (p = 0.003). Severe ulcer lesions significantly prevailed in the placebo group (p = 0.03). Locally invasive esophageal epithelial neoplasia were observed in 23/39 PPI-treated versus 14/42 placebo-animals (p = 0.03). In conclusion, chronic omeprazole treatment improved the healing of esophageal ulcerative lesions. Locally invasive neoplastic lesions and PACM prevailed among PPI-treated animals. However, neither an effect on the overall mortality nor on the incidence of pre-neoplastic lesions was observed in this work.

Combining formulation and process aspects for optimizing the high-shear wet granulation of common drugs.

The purpose of this research was to determine the effects of some important drug properties (such as particle size distribution, hygroscopicity and solubility) and process variables on the granule growth behaviour and final drug distribution in high shear wet granulation. Results have been analyzed in the light of widely accepted theories and some recently developed approaches. A mixture composed of drug, some excipients and a dry binder was processed using a lab-scale high-shear mixer. Three common active pharmaceutical ingredients (paracetamol, caffeine and acetylsalicylic acid) were used within the initial formulation. Drug load was 50% (on weight basis). Influences of drug particle properties (e.g. particle size and shape, hygroscopicity) on the granule growth behaviour were evaluated. Particle size distribution (PSD) and granule morphology were monitored during the entire process through sieve analysis and scanning electron microscope (SEM) image analysis. Resistance of the wet mass to mixing was furthermore measured using the impeller torque monitoring technique. The observed differences in the granule growth behaviour as well as the discrepancies between the actual and the ideal drug content in the final granules have been interpreted in terms of dimensionless quantity (spray flux number, bed penetration time) and related to torque measurements. Analysis highlighted the role of liquid distribution on the process. It was demonstrated that where the liquid penetration time was higher (e.g. paracetamol-based formulations), the liquid distribution was poorer leading to retarded granule growth and selective agglomeration. On the other hand where penetration time was lower (e.g. acetylsalicylic acid-based formulations), the growth was much faster but uniformity content problem arose because of the onset of crushing and layering phenomena.

Multidisciplinary approach on characterizing a mechanochemically activated composite of vinpocetine and crospovidone.

Significant improvement of solubilization kinetics of poorly soluble vinpocetine was obtained through a mechanochemical activation process in presence of micronized crospovidone. Drug-to-polymer weight ratio and milling time variables resulted to have statistically significant impacts on the activation of the product. The complete amorphization was obtained in the coground with the highest crospovidone contents (>80% wt), milled for the longest time (180 min). An ad hoc software was then used to calculate the dimensions of the drug crystallites in the samples on the basis of the calorimetric data. The thermal analyses were then accompanied and confirmed by an extensive solid-state characterization, performing X-ray diffraction, Raman imaging/spectroscopy, DRIFT, and SS-NMR spectroscopy, followed by laser diffraction and solubilization kinetics tests. All the analyses agreed on attesting the progressive loosing of crystalline structure of the drug when increasing milling time and amount of polymer in the formulations. This activated status of the drug, which resulted to be homogeneously distributed on the coground sample and stable for at least 1 year, was reflected on favorable solubilization kinetics. The in vivo studies on rats revealed that coground systems promoted a fivefold higher oral bioavailability enhancement in comparison to a commercial formulation (Vimpocetin 5mg Capsules, Pharma).

Simultaneous release and ADME processes of poorly water-soluble drugs: mathematical modeling.

The importance of studying oral drug absorption is well recognized by both research facilities/institutions and the pharmaceutical industry. The use of mathematical models can represent a very profitable and indispensable tool to understand oral drug absorption. Indeed, mathematical models can verify the correctness of the mechanisms proposed to describe drug release, absorption, distribution and elimination thus reducing the number of expensive and time-consuming experiments. In this paper we develop a mathematical approach able to model both the polymeric particle mediated delivery and the gastrointestinal absorption-metabolism-excretion (ADME) of a given drug. As a model drug a poorly water-soluble drug (vinpocetine) in both the amorphous and nanocrystalline state is considered. The delivery system is obtained by drug cogrinding with a polymer (cross-linked polyvinilpyrrolidone). As the proposed mathematical model can properly fit the in vivo data on the basis of information obtained in vitro, it represents a powerful theoretical tool connecting in vitro and in vivo behavior.

Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption.

A method of producing self-emulsifying pellets by wet granulation of powder mixture composed of microcrystalline cellulose, lactose and nimesulide as model drug with a mixture containing mono- and di-glycerides, polisorbate 80 and water, in a 10-l high shear mixer has been investigated. The effects of the formulation variables on pellets characteristics were evaluated by mixtures experimental design and by a polynomial model, in order to describe the phenomenon, to verify eventual interactions among components of the mixture and to investigate the feasibility of scaling-up. After determination of size distribution, the pellets were characterised by scanning electron microscopy, dissolution and disintegration tests, and by in vitro absorption test Such an approach, applied to the development of a self-emulsifying system for nimesulide as poorly water-soluble model drug, resulted in different formulations with improved drug solubility and permeability characteristics. The data demonstrate that pellets composed of oil to surfactant ratio of 1:4 (w/w) presented improvement in performance in permeation experiments.

Theoretical and experimental study on theophylline release from stearic acid cylindrical delivery systems.

The purpose of this study is to evaluate the possibility of developing a cylindrical sustained-release dosage form for theophylline directly by means of a ram extrusion process. In particular, the formulations contained: stearic acid as a low melting binder, monohydrate lactose and polyethylene glycol 6000 as hydrophilic fillers. The influence of type and percentage of the components was studied considering different parameters such as the time required for 50% of the drug release (t50%)and the drug diffusion coefficient in the delivery system. The choice of the different formulations to be tested is carried out employing an axial design with constraint domains. The limits of each component were fixed on the basis of preliminary trials. The analysis of the t50% values revealed that the release kinetics is mainly affected by stearic acid and theophylline content, whilst lactose effect is almost negligible. A substantial correspondence between the experimental results and the analysis of the drug release kinetics performed by means of an ad hoc developed mathematical model was found. The proposed mathematical model allows to conclude that wherever the release mechanism is initially ruled by dissolution, then diffusion plays the most important role.

Preparation and evaluation of a melt pelletised paracetamol/stearic acid sustained release delivery system.

The potential of a sustained release formulation for paracetamol produced by melt pelletisation was investigated. The chosen formulation was based on the combination of stearic acid as a melting binder and anhydrous lactose as a filler. After determination of the size distribution, the pellet characterisation included scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), specific surface area and true density determination. Hence, the in vitro release from every single size fraction (2000, 1250, 800, 630, <630 microm) was evaluated and the release mechanism was analysed with the help of an appropriate mathematical model. The results of drug content and superficial atomic composition were found to be constant in all pellets size fractions, attesting the ability of melt pelletisation in a high shear mixer to form a product with homogeneous composition. The mathematical model is built on the hypotheses that drug diffusion and solid drug dissolution in the release environment are the key phenomena affecting drug release kinetics. Smaller classes apart (particles are not perfectly spherical), the comparison between model best fitting and experimental data indicated the reasonability of these hypotheses. Moreover, model reliability is proved by its ability of predicting drug release from a known mixture of the above mentioned particles classes.