Design of a novel bilayered gastric mucoadhesive system for localized and unidirectional release of lamotrigine

Lamotrigine is a BCS class II drug with pH dependent solubility. The bilayered gastric mucoadhesive tablets of lamotrigine were designed such that the drug and controlled release polymers were incorporated in the upper layer and the lower layer had the mucoadhesive polymers. The major ingredients selected for the upper layer were the drug and control release polymer (either HPMC K15M or polyox) while the lower MA layer predominantly comprised of Carbopol 974P. A 2³ full factorial design was constructed for this study and the tablets were optimized for parameters like tablet size, shape, ex vivo mucoadhesive properties and unidirectional drug release. Oval tablets with an average size of 14 mm diameter were set optimum. Maximum mucoadhesive bond strength of 79.3 ± 0.91 * 10³ dyn/cm² was achieved with carbopol when used in combination with a synergistic resin polymer. All the tested formulations presented a mucoadhesion time of greater than 12 h. The incorporation of methacrylic polymers in the lower layer ensured unidirectional drug release from the bilayered tablets. The unidirectional drug release was confirmed after comparing the dissolution results of paddle method with those of a modified basket method. Model independent similarity and dissimilarity factor methods were used for the comparison of dissolution results. Controlled drug release profiles with zero order kinetics were obtained with polyox and HPMC K15M which reported t_90% at 6th and 12th hours, respectively. The “n” value with polyox was 0.992 and that with HPMC K15M was 0.946 indicating an approximate case II transport. These two formulations showed the potential for oral administration of lamotrigine as bilayered gastric mucoadhesive tablets by yielding highest similarity factor values, 96.06 and 92.47, respectively, between the paddle and modified basket method dissolution release profiles apart from reporting the best tablet physical properties and maximum mucoadhesive strength.     

Design,synthesis and in vitro evaluation of mucoadhesive p-coumarate-thiolated-chitosan as a hydrophobic drug carriers

A hydrophobic mucoadhesive thiolated chitosan for hydrophobic drug delivery was designed and prepared by conjugating p-coumaric acid (pCA) to increase hydrophobic compatibility with drug via pi–pi interaction and then covalently linking homocysteine thiolactone (HT) to the pCA-chitosan to increase the mucoadhesive properties. The degree of substituted phenolics in the modified chitosan was about 7.21 ± 0.05 mg gallic acid equivalents (GAE)/g. The pCA-HT-chitosan formed from a 24 h HT conjugation reaction time showed the highest yield of grafted thiol groups (∼17.6 μmol/g) and the strongest mucoadhesive property, being about 10-, 2- and 1.6-fold more than that for the unmodified chitosan at pH 1.2, 4.0 and 6.4, respectively. Piperine (PIP) as a model hydrophobic drug was encapsulated in pCA-HT-chitosan microparticles via electrospray ionization with an encapsulation efficiency of over 80%. In vitro release studies showed a sustained release of PIP to >75% over 12 h between pH 1.2 and 6.4.     

A new mucoadhesive dosage form for the management of oral lichen planus: Formulation study and clinical study

The work aimed at studying a new mucoadhesive prolonged release tablet containing 24 μg clobetasol-17 propionate (CP) suitable for the management of oral lichen planus. Low swellable dosage forms were designed by combining a mucoadhesive polymer, i.e. poly(sodium methacrylate, methylmethacrylate), with hydroxypropylmethylcellulose and MgCl₂. This formulation was selected to modify the tablet erosion rate in order to obtain a release of CP over a 6-h period. A double-blind, controlled study was performed using three groups of patient (n = 16) who received three applications-a-day over 4 weeks of the developed CP tablets (group CP-T), placebo tablets (group CP-P) or commercial CP ointment for cutaneous application (123 μg/application) extemporary mixed with Orabase™ (group CP-O). At the end of the study, pain and ulceration resolved in 13/16 and 11/16 patients of group CP-T and group CP-O, respectively. In the group CP-O, a transient acute hyperaemic candidosis (n = 2) and taste alteration (n = 4) were also observed. No changes in clinical signs of patients in the group CP-P were evident. The application of mucoadhesive tablet containing 24 μg CP 3 times a day appeared to be effective, avoiding the side effects of the generally used treatment.     

Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting

The estradiol(E₂)-loaded chitosan nanoparticles (CS-NPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP). The CS-NPs had a mean size of (269.3 ± 31.6) nm, a zeta potential of +25.4 mV, and loading capacity of E₂ CS-NPs suspension was 1.9 mg ml⁻¹, entrapment efficiency was 64.7% on average. Subsequently, this paper investigated the levels of E₂ in blood and the cerebrospinal fluid (CSF) in rats following intranasal administration of E₂ CS-NPs. E₂-loaded CS-NPs were administered to male Wister rats either intranasally or intravenously at the dose of 0.48 mg kg⁻¹. The plasma levels achieved following intranasal administration (32.7 ± 10.1 ng ml⁻¹; t_max 28 ± 4.5 min) were significantly lower than those after intravenous administration (151.4 ± 28.2 ng ml⁻¹), while CSF concentrations achieved after intranasal administration (76.4 ± 14.0 ng ml⁻¹; t_max 28 ± 17.9 min) were significantly higher than those after intravenous administration (29.5 ± 7.4 ng ml⁻¹ t_max 60 min). The drug targeting index (DTI) of nasal route was 3.2, percent of drug targeting (DTP%) was 68.4%. These results showed that the E₂ must be directly transported from the nasal cavity into the CSF in rats. Finally, compared with E₂ inclusion complex, CS-NPs improved significantly E₂ being transported into central nervous system (CNS).     

Preparation and evaluation of mucinated sodium alginate microparticles for oral delivery of insulin

Effective oral insulin delivery remains a challenge to the pharmaceutical industry. In this study, insulin-loaded microparticles for oral delivery were prepared with mucin and sodium alginate combined at different ratios using a novel method based on polymer coacervation and diffusion filling. Some physical characteristics of the various insulin-loaded microparticles such as particle size, morphology and compressibility indices were determined. The microparticles were filled into hard gelatin capsules and the in vitro insulin release as well as the blood glucose reduction after oral administration to diabetic rabbits were determined. The microparticles formed were generally multi-particulate, discrete and free flowing. Before insulin loading, microparticles were round and smooth, becoming fluffier, less spherical and larger with rough and pitted surface after insulin loading. The insulin content of the microparticles increased with increase in their sodium alginate content. The various insulin-loaded microparticles prepared with the mucinated sodium alginate when encapsulated exhibited lag time before insulin release. The time taken to reach maximum insulin release from the various formulations varied with the mucin–sodium alginate ratio mix. The mean dissolution time of insulin from the microparticles prepared with sodium alginate, mucin, sodium alginate: mucin ratios of 1:1, 3:1 and 1:3 was 11.21 ± 0.75, 3.3 ± 0.42, 6.69 ± 023, 8.52 ± 0.95 and 3.48 ± 0.65 (min.), respectively. The percentage blood glucose reduction for the subcutaneously administered insulin was significantly (p < 0.001) higher than for the formulations. The blood glucose reduction effect produced by the orally administered insulin-loaded microparticles prepared with three parts of sodium alginate and one part of mucin after 5 h was, however, equal to that produced by the subcutaneously administered insulin solution, an indication that it is an effective alternative for the delivery of insulin.     

Mucoadhesive microparticles as potential carriers in inhalation delivery of doxycycline hyclate: a comparative study

The present work compares and evaluates the suitability of different polymer-based microparticles for inhalation delivery of doxycycline hyclate. Mucoadhesive polymers, such as sodium carboxymethyl cellulose, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, starch, and carbopol were selected as carriers for inhalation delivery. Microparticles were prepared by spray drying and evaluated in terms of yield, moisture content, morphology, tapped density, encapsulation efficiency, in vitro mucoadhesion, thermal properties and in vitro aerosolization performance. Additionally, the cytotoxicity of the microparticles on H1299 human alveolar cell line was examined. Smooth spherical to collapsed doughnut shaped particles were formed. They exhibited tap densities of 0.202–0.502 g/cm³ and mass median aerodynamic diameter of 3.74–6.54 μm. Mucoadhesion was highest in case of carbopol-based microparticles. Drug release from these microparticles exhibited biphasic Fickian type of diffusion. Only at the highest concentration of microparticles (1 mg/mL) less than 90% cell viability was seen in DX loaded sodium alginate microparticles (DXSA, 87.2%), starch microparticles (DXST, 85.1%) and carbopol microparticles (DXCP, 82.7%) preparations after 48 h of exposure to alveolar cells. The results clearly indicate that sodium carboxymethyl cellulose-based microparticles may serve as an ideal carrier for inhalation delivery of doxycycline hyclate.     

Novel dual-reverse thermosensitive solid lipid nanoparticle-loaded hydrogel for rectal administration of flurbiprofen with improved bioavailability and reduced initial burst effect

The purpose of this study was to develop novel solid lipid nanoparticle (SLN)-loaded dual-reverse thermosensitive hydrogel (DRTH) for rectal administration of flurbiprofen with improved bioavailability and reduced initial burst effect. The flurbiprofen-loaded SLNs were prepared by hot homogenisation technique, after optimising the amounts of lipid mixture (tricaprin and triethanolamine in 8:2 weight ratio), drug and surfactant. The flurbiprofen-loaded thermosensitive SLN composed of drug, lipid mixture and surfactant at a weight ratio of 10/15/1.3 was a solid at room temperature, and changed to liquid form at physiological temperature due to its melting point of about 32 °C. This SLN gave the mean particle size of about 190 nm and entrapment efficiency of around 90%. The DRTHs were prepared by adding this flurbiprofen-loaded thermosensitive SLN in various poloxamer solutions. Their rheological characterisation, release and stability were investigated while a morphological and pharmacokinetic study was performed after its rectal administration to rats compared with the drug and hydrogel. Poloxamer 188 and SLN decreased the gelation temperature and gelation time, but increased the viscosity at 25 °C, gel strength and mucoadhesive force of DRTHs. In particular, the DRTH composed of [SLN/P 407/P 188 (10%/15%/25%)] with the gelation temperature of about 35 °C existed as liquid at room temperature, but gelled at 30–36 °C, leading to opposite reversible property of SLN. Thus, it was easy to administer rectally, and it gelled rapidly inside the body. This DRTH gave a significantly increased dissolution rate of the drug as compared to the flurbiprofen, but significantly retarded as compared to the hydrogel, including the initial dissolution rate. Moreover, this DRTH gave significantly higher plasma concentration and 7.5-fold AUC values compared to the drug, and lower initial plasma concentration and C_max value compared to the hydrogel due to reduced initial burst effect. No damage in rectal mucosa was observed after the application of DRTH. Thus, this DRTH system with improved bioavailability and reduced initial burst effect would be recommended as an alternative for the flurbiprofen-loaded rectal pharmaceutical products.     

Reduction in burst release of PLGA microparticles by incorporation into cubic phase-forming systems

A high initial burst release of an phosphorothioate oligonucleotide drug from poly(lactide-co-glycolide) (PLGA) microparticles prepared by the w/o/w solvent extraction/evaporation was reduced by incorporating the microparticles into the following glycerol monooleate (GMO) formulations: 1) pure molten GMO, 2) preformed cubic phase (GMO + water) or 3) low viscosity in situ cubic phase-forming formulations (GMO + water + cosolvent). The in situ cubic phase-forming formulations had a low viscosity in contrast to the first two formulations resulting in good dispersability of the microparticles and good syringability/injectability. Upon contact with an aqueous phase, a highly viscous cubic phase formed immediately entrapping the microparticles. A low initial burst and a continuous extended release over several weeks was obtained with all investigated formulations. The drug release profile could be well controlled by the cosolvent composition with the in situ systems.     

Solid Lipid Microparticles for the Stability Enhancement of a Dopamine Prodrug

The oral or peripheral administration of dopamine for the treatment of Parkinson’s disease is hampered by its extensive metabolism and inability to cross the blood-brain barrier. Consequently, the enhancement of dopamine stability in physiologic environments and its brain targeting appear useful in formulation development. We propose the preparation and characterization of solid lipid microparticles based on tristearin as a sustained delivery system for dopamine. The microparticles were produced by conventional hot emulsion techniques. The synthesis of a new valeroyl ester of dopamine (3,4-O-divaleroyl-dopamine, DVD) was necessary to obtain its encapsulation in the microparticles. DVD appeared totally hydrolyzed to dopamine in human plasma within 40 s. The amount of encapsulated DVD in microparticles was 2.67 ± 1.2%. The mean diameter of particles was 14.2 ± 4.8 mm. The DVD release from microparticles was characterized by an initial burst of 20% of incorporated prodrug and a continuous slow release thereafter. The microparticles were able to stabilize DVD in its solid form. In human plasma, DVD encapsulated in microparticles hydrolyzed with a markedly reduced rate in comparison with free prodrug: after 15 min, 35.8% of DVD was still detectable. The DVD-loaded microparticles could represent a potential system for dopamine uptake in the brain, following nasal administration. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4730–4737, 2010     

Formulation and physicochemical characterisation of buccoadhesive films containing ketorolac

Ketorolac tromethamine, the non-steroidal anti-inflammatory drug, was formulated onto buccoadhesive films to overcome the limitations in the currently available dosage and routes of administration which in sequence will increase patients’ compliance. Films were cast from organic and aqueous solvents using various bioadhesive polymers namely: sodium carboxymethyl cellulose (Na-CMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC) and Carbopol 934. The prepared films were subjected to investigations for their physical and mechanical properties, swelling behaviors, in vitro bioadhesion, drug permeation via bovine buccal mucosa and in vitro drug release. These properties were found to vary significantly depending on the preparation methods, the type of the polymers and the ratio of addition of both plasticizer (i.e. polyethylene glycol) and film forming agent (ethyl cellulose and polyvinylpyrolidene). Formula number K10 containing carbopol 0.5% and HPMC 0.5% was found to be the best film as it shows good adhesion, acceptable pH, and gives a reasonable ketrolac release (about 85-90% at 6 h). In addition, this film was subjected to in vitro and in vivo release. The obtained results indicate that the concentration of ketorolac in the oral cavity was maintained above 4.0 μg/mL for a period of at least 6 h. This film shows promising results for using the ketrolac buccoadhesive route of administration topically and systemically, and thus it will be subjected to clinical evaluation in future work.     

Superparamagnetic iron oxide nanoparticles (SPIONs)-loaded Trojan microparticles for targeted aerosol delivery to the lung

Targeted aerosol delivery to specific regions of the lung may improve therapeutic efficiency and minimise unwanted side effects. Targeted delivery could potentially be achieved with porous microparticles loaded with superparamagnetic iron oxide nanoparticles (SPIONs)—in combination with a target-directed magnetic gradient field. The aim of this study was to formulate and evaluate the aerodynamic properties of SPIONs-loaded Trojan microparticles after delivery from a dry powder inhaler. Microparticles made of SPIONs, PEG and hydroxypropyl-β-cyclodextrin (HPβCD) were formulated by spray drying and characterised by various physicochemical methods. Aerodynamic properties were evaluated using a next generation cascade impactor (NGI), with or without a magnet positioned at stage 2. Mixing appropriate proportions of SPIONs, PEG and HPβCD allowed Trojan microparticle to be formulated. These particles had a median geometric diameter of 2.8 ± 0.3 μm and were shown to be sensitive to the magnetic field induced by a magnet having a maximum energy product of 413.8 kJ/m³. However, these particles, characterised by a mass median aerodynamic diameter (MMAD) of 10.2 ± 2.0 μm, were considered to be not inhalable. The poor aerodynamic properties resulted from aggregation of the particles. The addition of (NH₄)₂CO₃ and magnesium stearate (MgST) to the formulation improved the aerodynamic properties of the Trojan particles and resulted in a MMAD of 2.2 ± 0.8 μm. In the presence of a magnetic field on stage 2 of the NGI, the amount of particles deposited at this stage increased 4-fold from 4.8 ± 0.7% to 19.5 ± 3.3%. These Trojan particles appeared highly sensitive to the magnetic field and their deposition on most of the stages of the NGI was changed in the presence compared to the absence of the magnet. If loaded with a pharmaceutical active ingredient, these particles may be useful for treating localised lung disease such as cancer nodules or bacterial infectious foci.     

Thiolated hydroxyethylcellulose: Synthesis and in vitro evaluation

In recent years, thiomers have received considerable interest due to advantageous characteristics, such as improved mucoadhesive and permeation enhancing properties. Thiolated polymers, however, are characterized by an ionic charge which represents for various applications a great limitation. The aim of this study was therefore to synthesize a novel thiolated polymer not exhibiting ionizable groups. Hydroxyethylcellulose (HEC) was chosen as polymer backbone. The chemical modification was achieved by the replacement of hydroxyl groups on the carbohydrate structure with thiol moieties, using thiourea as thiolating reagent. The resulting thiolated hydroxyethylcellulose (HEC-SH) was characterized in vitro regarding its gelling properties, swelling behaviour, mucoadhesion on freshly excised porcine intestinal mucosa and permeation enhancing effect across rat intestinal mucosa. The new thiomer displayed up to 131.58 ± 11.17 μmol thiol groups per gram polymer, which are responsible for the observed in situ gelling capacity. The swelling behaviour and the mucoadhesive properties of tablets based on HEC-SH were 1.5-fold and 4-fold improved compared with unmodified HEC, respectively. The permeation enhancing effect of 0.5% (m/v) HEC-SH on rhodamine 123 (Rho-123) transport was 1.9-fold improved compared with buffer only. According to these results, HEC-SH seems to represent a promising tool for the development of in situ gelling, mucoadhesive delivery systems with permeation enhancing properties.     

Development of Mucoadhesive Films for Buccal Administration of Flufenamic Acid: Effect of Cyclodextrin Complexation

A new mucoadhesive film for topical administration in the oral cavity of flufenamic acid, a poorly soluble anti-inflammatory drug, has been developed, using complexation with hydroxypropyl-β-cyclodextrin (HPβCD) to improve drug dissolution and release rate. Buccal films were prepared utilising chitosan as mucoadhesive polymer, KollicoatIR® as film-forming polymer and glycerol as plasticiser. Different combinations of these components were used and the obtained films were characterised for weight, thickness, swelling, mucoadhesive and mechanical properties. The film containing chitosan 2%, glycerol 7.5% and KollicoatIR® 1% showed the best properties for the development of the film formulation. The selected film was loaded with the plain drug and its colyophilised and coground products with HPβCD, and in vitro release studies in simulated saliva were performed. The improved drug dissolution properties, obtained by complexation with HPβCD, were critical to achieve complete release from film formulation during 4–5 h. On the contrary, film loaded with the plain drug showed incomplete release, not exceeding 70% release after 5 h. The developed film formulation containing the drug as complex with HPβCD can assure a prolonged drug release directly at the inflammation site and can be proposed as a new therapeutic tool in the treatment of oral mucosa inflammations.     

A novel dense CO2 supercritical fluid technology for the development of microparticulate delivery systems containing ketoprofen

VarioSol® is an innovative, solvent-free technology able to produce microparticles exploiting near-critical CO₂ properties as spraying and cooling agent. The aim of the present work was to evaluate the feasibility to produce in a single processing step by VarioSol® technology, oral ketoprofen-loaded microparticles with gastro-protective properties. The obtained products were powders composed of regular in shape and small in diameter microparticles, characterized by high drug content (40%) and good flow properties. Microparticles were composed by anionic lipids scarcely soluble at acidic pH, blended with gastro-resistant polymers of the methacrylate type. In vitro drug release results indicated that the drug was rapidly delivered from the microparticulate systems in phosphate buffer at pH 6.8, while in acidic medium, the microparticles were able to retard the drug release process but without reaching complete gastro-resistance.However, the results obtained in this study, although non optimal, are not far from the specifications required for gastro-resistant release products (i.e., no more than 10% drug released after 1 h at pH 1.0) according to EMA guidelines and represent a good starting point for future formulation development.     

Release of Prednisolone and Inulin from a New Calcium-Alginate Chitosan-Coated Matrix System for Colonic Delivery

Putative colonic release formulations of calcium (Ca)-alginate coated with chitosan containing two different actives, prednisolone and inulin, were prepared in three different sizes, beads (D₅₀ = 2104 μm) and microparticles (D₅₀ = 354 and 136 μm). The formulations were tested in standard phosphate buffer and biorelevant Krebs bicarbonate buffer at pH 7.4, and were further evaluated in the presence of the bacterium E. coli. Product yield and encapsulation were higher with prednisolone than with inulin. In Krebs bicarbonate buffer, a clear relationship between particle size and prednisolone release was observed. In contrast, release of inulin was independent of the particle size. In phosphate buffer, the particles eroded quickly, whereas in Krebs buffer, the particles swelled slowly. The difference in behavior can be attributed to the formation of calcium phosphate in the phosphate buffer medium, which in turn weakens the Ca-alginate matrix core. In the presence of E. coli, the formulations were fermented and the release of prednisolone was accelerated. In conclusion, the buffer media affects formulation behavior and drug release, with the bicarbonate media providing a better simulation of in vivo behavior. Moreover, the susceptibility of the formulations to bacterial action indicates their suitability as carriers for colonic drug delivery.     

Evaluation of spray congealing as technique for the preparation of highly loaded solid lipid microparticles containing the sunscreen agent,avobenzone

Solid lipid microparticles (SLMs) loaded with high amounts of the sunscreen agent, butyl methoxydibenzoylmethane (avobenzone) were prepared in order to reduce its photoinstability. The microparticles were produced, using carnauba wax as lipidic material and phosphatidylcholine as the surfactant, by the classical melt dispersion method or the spray congealing technique with pneumatic atomizer. The sunscreen agent loading was 40.1–48.5% (w/w), with no significant differences between the production methods. However, release studies indicated that spray congealing enabled a more efficient modulation of avobenzone release from the SLMs (26% of encapsulated avobenzone released after 2 h as compared to 60% for melt dispersion). The photoprotective efficacy of the SLMs was evaluated after their introduction in a model cream. A statistically significant decrease of the light-induced degradation of avobenzone was obtained by the SLMs prepared by the melt dispersion procedure (the extent of degradation was 38.6 ± 3.6% for nonencapsulated avobenzone and 32.1 ± 4.3% for the microparticle-entrapped sunscreen). On the other hand, the SLMs produced by spray congealing achieved a more marked reduction in avobenzone photodecomposition to 15.4 ± 4.1%. Therefore, the spray congealing technique was superior to the classical melt dispersion method for rapid and solvent free production of SLMs with a high avobenzone loading capacity. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2759–2769, 2009     

Determination of dependencies among in vitro and in vivo properties of prepared mucoadhesive buccal films using multivariate data analysis

Mucoadhesive films represent the most developed medical form of buccal application. Despite the intense focus on buccal film-based systems, there are no standardized methods for their evaluation, which limits the possibility of comparison of obtained data and evaluation of the significance of influence of formulation and process variables on properties of resulting films. The used principal component analysis, together with a partial least squares regression provided a unique insight into the effects of in vitro parameters of mucoadhesive buccal films on their in vivo properties and into interdependencies among the studied variables. In the present study eight various mucoadhesive buccal films based on mucoadhesive polymers (carmellose, polyethylene oxide) were prepared using a solvent casting method or a method of impregnation, respectively. An ethylcellulose or hydrophobic blend of white beeswax and white petrolatum were used as a backing layer. The addition of polyethylene oxide prolonged the in vivo film residence time (from 53.24 ± 5.38–74.18 ± 5.13 min to 71.05 ± 3.15–98.12 ± 1.75 min), and even more when combined with an ethylcellulose backing layer (98.12 ± 1.75 min) and also improved the film’s appearance. Tested non-woven textile shortened the in vivo film residence time (from 74.18 ± 5.13–98.12 ± 1.75 min to 53.24 ± 5.38–81.00 ± 8.47 min) and generally worsened the film’s appearance. Mucoadhesive buccal films with a hydrophobic backing layer were associated with increased frequency of adverse effects.     

Design of a gastroretentive mucoadhesive dosage form of furosemide for controlled release

The aim of the present study was to develop and characterize a gastroretentive dosage form suitable for controlled drug release. It consists of a drug loaded polymeric film made up of a bilayer of immediate (IR) and controlled release (CR) layers folded into a hard gelatin capsule. Gastroretention results from unfolding and swelling of the film and its bioadhesion to the gastric mucosa. Furosemide, a drug with a narrow absorption window, was selected as the model drug. Inclusion of hydroxypropyl β-cyclodextrin in both layers and Carbopol^® 971P NF in the CR layer of the bilayer film resulted in optimum drug release, bioadhesion and mechanical properties. The film with zig-zag folding in the capsule was shown to unfold and swell under acidic conditions and provide IR of drug over 1 h and CR for up to 12 h in acidic medium. X-ray diffraction, differential scanning calorimetry and scanning electron microscopy revealed uniform dispersion of furosemide in the polymeric matrices. The results indicate the dosage form is gastroretentive and can provide controlled release of drugs with narrow therapeutic windows.     

Inhibiting the Gastric Burst Release of Drugs from Enteric Microparticles: The Influence of Drug Molecular Mass and Solubility

Undesired drug release in acid medium from enteric microparticles has been widely reported. In this paper, we investigate the relative contribution of microparticle and drug properties, specifically microsphere size and drug’s molecular weight and acid solubility, on the extent of such undesired release. A series of nine drugs with different physicochemical properties were successfully encapsulated into Eudragit S and Eudragit L microparticles using a novel emulsion solvent evaporation process. The process yielded spherical microparticles with a narrow size distribution (27–60 and 36–56 mm for Eudragit L and Eudragit S microparticles, respectively). Upon incubation in acid medium (pH 1.2) for 2 h, the release of dipyridamole, cinnarizine, amprenavir, bendroflumethiazide, budesonide and prednisolone from both Eudragit microparticles was less than 10% of drug load and conformed with the USP specifications for enteric dosage forms. In contrast, more than 10% of the entrapped paracetamol, salicylic acid and ketoprofen were released. Multiple regression revealed that the drug’s molecular weight was the most important factor that determined its extent of release in the acid medium, while its acid solubility and microsphere’s size had minor influences.     

Polymer–lipid based mucoadhesive microspheres prepared by spray-congealing for the vaginal delivery of econazole nitrate

This research aimed to evaluate a new approach for the preparation of mucoadhesive microparticles and to design an innovative vaginal delivery systems for econazole nitrate (ECN) able to enhance the drug antifungal activity.Seven different formulations were prepared by spray-congealing: a lipid–hydrophilic matrix (Gelucire^® 53/10) was used as carrier and several mucoadhesive polymers such as chitosan, sodium carboxymethylcellulose and poloxamers (Lutrol^® F68 and F127) were added. All microparticles were characterized and compared for morphology, particle size, drug loading and solubility in simulated vaginal fluid, bioadhesion to mucosal tissue, dissolution behaviour and for their physicochemical properties. The antifungal activity of the microparticles against a strain of Candida albicans ATCC 10231 was also investigated.Non-aggregated microspheres with high yields (>90%, w/w) and with prevalent size in the range 100–355 μm were obtained. Both poloxamers significantly (p < 0.01) improved the solubility and in vitro bioavailability of the low solubility drug and the mucoadhesive strength. Poloxamers/Gelucire^®-based microparticles exhibited an inhibition effect on the C. albicans growth, suggesting their use as an effective treatment for vaginal candidiasis, with potential for reduced administration frequency.In conclusion the results demonstrated that spray-congealing technology can be considered a novel and solvent-free approach for the production of mucoadhesive microparticles for the vaginal delivery of ECN.