A Laminated Polymer Film Formulation for Enteric Delivery of Live Vaccine and Probiotic Bacteria

Live bacterial cells (LBCs) are administered orally as attenuated vaccines to deliver biopharmaceutical agents and as probiotics to improve gastrointestinal (GI) health. However, LBCs present unique formulation challenges and must survive GI antimicrobial defenses including gastric acid after administration. We present a simple new formulation concept, termed polymer film laminate (PFL). LBCs are ambient dried onto cast acid-resistant enteric polymer films that are then laminated together to produce a solid oral dosage form. LBC of a model live bacterial vaccine and a probiotic were dried directly onto a cast film of enteric polymer. The effectiveness at protecting dried cells in a simulated gastric fluid (SGF, pH 2.0) depended on the composition of enteric polymer film used, with a blend of ethylcellulose plus Eudragit L100 55 providing greater protection from acid than Eudragit alone. However, although PFL made from blended polymer films completely released low-molecular-weight dye into intestinal conditions (pH 7.0), they failed to release LBCs. In contrast, PFL made from Eudragit alone successfully protected dried probiotic or vaccine LBC from SGF for 2 h, and subsequently released all viable cells within 60 min of transfer into simulated intestinal fluid. Release kinetics could be controlled by modifying the lamination method.     

Novel pH-Sensitive Lipid-Polymer Composite Microspheres of 10-Hydroxycamptothecin Exhibiting Colon-Specific Biodistribution and Reduced Systemic Absorption

Novel lipid-polymer composite microspheres (LP-MS) were prepared by combining pH-sensitive polymer Eudragit S100 with solid lipid Compritol 888 ATO for colonic delivery of 10-hydroxycamptothecin (HCPT), and pH-dependent controlled drug release has been achieved. The colon-specific biodistribution and uptake by the mucosal tissue were examined using coumarin-6-marked LP-MS. It is proved that good in vitro-in vivo relationship has been achieved, with more drugs being delivered to colon and a higher drug level was maintained for a long period. Moreover, in vivo bioavailability of LP-MS was evaluated with conventional enteric microspheres (enteric MS) as reference. After administration of LP-MS, systemic absorption of HCPT was greatly reduced, with area under the curve from 0 to 24 h (AUC_0 -24h, 2.186 ± 0.27) being significantly lower than that of enteric MS group (6.352 ± 0.696). In conclusion, the novel pH-sensitive LP-MS has potential for colon-specific drug delivery.     

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.     

The use of dynamic mechanical analysis (DMA) to evaluate plasticization of acrylic polymer films under simulated gastrointestinal conditions

PurposeGlass transition temperature (T_g) measurements of polymers are conventionally conducted in the dry state with little attention to the environment they are designed to work in. Our aim was to develop the novel use of dynamic mechanical analysis (DMA) to measure the T_g of enteric polymethacrylic acid methylmethacrylate (Eudragit L and S) polymer films formulated with a range of plasticizers in the dry and wet (while immersed in simulated gastric media) states.MethodsPolymer films were fabricated with and without different plasticizers (triacetin, acetyl triethyl citrate, triethyl citrate, polyethylene glycol, propylene glycol, dibutyl phthalate, dibutyl sebacate). T_g was measured by a dynamic oscillating force with simultaneous heating at 1 °C/min. This was conducted on films in the dry state and while immersed in 0.1 M HCl to simulate the pH environment in the stomach.ResultsThe T_g of unplasticized Eudragit L and S films in the dry state was measured to be 150 and 120 °C, respectively. These values were drastically reduced in the wet state to 20 and 71 °C for Eudragit L and S films, respectively. The plasticized films showed similar falls in T_g in the wet state. The fall in T_g of Eudragit L films to below body temperature will have far-reaching implications on polymer functionality and drug release.ConclusionsImmersion DMA provides a robust method for measuring T_g of polymer films in the wet state. This allows better prediction of polymer behaviour in vivo.     

Spray-drying enteric polymers from aqueous solutions: A novel, economic, and environmentally friendly approach to produce pH-responsive microparticles

We describe a novel method to fabricate pH-responsive microparticles suitable for oral delivery using an aqueous-based spray-drying approach. The approach involves the neutralization and generation of water-soluble salt forms of enteric polymers. The methacrylic acid polymers (Eudragit L and Eudragit S) were added separately to aqueous solutions of ammonium hydrogen carbonate; the solutions were then spray-dried. FTIR analysis of the harvested microparticle products identified the presence of ammonium methacrylate with the appearance of a peak at 1550 cm⁻¹ corresponding to the stretching of the N–H bond. Incubating the microparticles for three hours at 70 °C and 130 °C for the Eudragit S and L products, respectively, was sufficient to eradicate the ammonium residues. The microparticles, loaded with the model drug prednisolone, were spherical and small in size (2–5 μm). Moreover, the particles were gastro-resistant, and release was rapid and complete at small intestinal conditions. The pH threshold of release of the Eudragit S and Eudragit L microparticles was lowered from 7 and 6 to 6.5 and 5.5, respectively. In bicarbonate media, which are physiological and representative of the conditions of the proximal small intestine (mHanks) and the distal small intestine (Kreb’s), drug release from these spray-dried microparticles was faster compared to microparticles produced from conventional emulsion solvent evaporation methods. This new microparticle preparation concept obviates the need for organic solvents and utilizes spray-drying techniques that are amenable to industrial application; the approach therefore offers economic, safety, and environmental benefits.     

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.     

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.     

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     

An approach for lacidipine loaded gastroretentive formulation prepared by different methods for gastroparesis in diabetic patients

The present work deals with various attempts to prepare a gastroretentive formulation of lacidipine for treating gastroparesis. High density sucrose beads were modified by coating with certain polymers, but unfortunately sustained release could not be achieved. Granules were prepared by wet granulation technology using different combinations of polymers and a release of the drug was observed. The method failed to release the drug as per desired specifications. Polymeric coating followed by wet granulation was thought to be a better process to sustain the dissolution rate. The release rate can be modified by the incorporation of different polymeric coatings, but the mucoadhesive potential of granules was only 4.23% which might be due to its large size and the presence of other ingredients. Further, the lacidipine loaded microparticles were prepared by different methods such as compression, ionic gelation with TPP, ionic gelation with TPP and glutaraldehyde, spray drying and coacervation techniques. The formulations were evaluated for average particle size, surface morphology, entrapment efficiency, % yield and mucoadhesive potential. The microparticles prepared by compression method using HPMC K4M and SCMC as mucoadhesive polymers and BaSO₄ as high density diluent showed poor bioadhesion (8.3%) and poor release characteristics (100% in 120 min). Ionic gelation with tripolyphosphate yielded microspheres with poor mechanical strength. In order to improve its mechanical strength, TPP ionic gelation was combined with step-wise cross-linking with glutaraldehyde. The additional solidification step to improve mechanical strength left this procedure tedious, time consuming and cytotoxic. Spray drying method gave a very low yield with 46.67% bioadhesion. The method using CaCl₂ for ionotropic gelation showed the best results with regard to physical characteristics (well formed discrete, spherical surface microcapsule), particle size (88.57 ± 0.51), in vitro bioadhesion (67.33%), yield (>85%) and loading (>70%).     

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 novel once daily microparticulate dosage form comprising lansoprazole to prevent nocturnal acid breakthrough in the case of gastro-esophageal reflux disease: preparation,pharmacokinetic and pharmacodynamic evaluation

The objective of this study was to formulate and evaluate the lansoprazole (LPZ)-loaded microparticles to prevent nocturnal acid breakthrough in the case of gastro-esophageal reflux disease (GERD). The microparticulate delivery system was prepared by solvent evaporation method using Eudragit RS100 as a matrix polymer followed by enteric coated with Eudragit S100 and hydroxypropyl methylcellulose phthalate HP55 using spray drying method. The enteric coated microparticles were stable in gastric pH condition. In vivo pharmacokinetic and pharmacodynamic studies in male Wistar rats demonstrated that enteric coated microparticles sustained release of LPZ and promoted ulcer healing activity. In other words, the microparticulate dosage form provided effective drug concentration for a longer period as compared to conventional extended release dosage form, and showed sufficient anti-acid secretion activity to treat acid related disorders including the enrichment of nocturnal acid breakthrough event based on a once daily administration.     

Synthesis and evaluation of chitosan-graft-poly (2-hydroxyethyl methacrylate-co-itaconic acid) as a drug carrier for controlled release of tramadol hydrochloride

Chitosan-graft-poly (2-hydroxyethyl methacrylate-co-itaconic acid) has been synthesized for different feed ratios of 2-hydroxyethyl methacrylate and itaconic acid and characterized by FT-IR, thermogravimetry and swelling in simulated biological fluids (SBF) and evaluated as a drug carrier with model drug, tramadol hydrochloride (TRM). Grafting decreased the thermal stability of chitosan. FT-IR spectra of tablet did not reveal any molecular level (i.e. at <10 nm scale) drug–polymer interaction. But differential scanning calorimetric studies indicated a probable drug–polymer interaction at a scale >100 nm level. The observed Korsmeyer–Peppas’s power law exponents (0.19–1.21) for the in vitro release profiles of TRM in SBF and other drugs such as 5-fluorouracil (FU), paracetamol (PCM) and vanlafaxine hydrochloride (VNF) with the copolymer carriers revealed an anomalous drug release mechanism. The decreased release rates for the grafted chitosan and the enhanced release rate for the grafts with increasing itaconic acid content in the feed were more likely attributed to the enhanced drug–matrix interaction and polymer–SBF interactions, respectively. The different release profiles of FU, PCM, TRM and VNF with the copolymer matrix are attributed to the different chemical structures of drugs. The above features suggest the graft copolymer’s candidature for use as a promising oral drug delivery system.     

Development of pH- and time-dependent oral microparticles to optimize budesonide delivery to ileum and colon

A microparticulate system consisting of non-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core and delivering budesonide site specifically to distal ileum and colon was developed. Budesonide-loaded microparticles were fabricated using solvent evaporation technique and formulation variables studied included different molecular weight grades of PLGA polymer as well as concentration of polymer, surfactant and drug. Eudragit S-100, an enteric polymer, was then used to form a coating on the surface of budesonide-loaded PLGA microparticles for site specific delivery to the distal ileum and colon. Budesonide-loaded PLGA microparticles prepared from various formulation parameters showed mean encapsulation efficiencies ranging between 50% and 85% and mean particle size ranging between 10 and 35mum. In vitro release kinetics studies showed a biphasic release pattern with an initial higher release followed by a slower drug release. Increasing polymer and surfactant concentrations exhibited sharply contrasting drug release profiles, with increasing polymer concentrations resulting in a lower drug release and vice versa. The budesonide-loaded PLGA microparticles coated with Eudragit S-100 coating showed a decrease in entrapment efficiency with an accelerated in vitro drug release. Moreover, complete retardation of drug release in an acidic pH, and, once the coating layer of enteric polymer was dissolved at higher pH (7.4 and 6.8), a controlled release of the drug from the microparticles were observed. From the results of this investigation, the application of double microencapsulation technique employing PLGA matrix and Eudragit S-100 coating shows promise for site specific and controlled delivery of budesonide in Crohn's disease.     

Comparative pharmaceutical study on colon targeted micro-particles of celecoxib: in-vitro–in-vivo evaluation

In order to target celecoxib which is a COX2 inhibitor, with potentials in the prevention and treatment of colitis and colon cancer, it was formulated as microparticles using the solvent/evaporation method and various pH-dependent Eudragit polymers. The in-vitro evaluation of the prepared microparticles showed spherical and smooth morphology. The encapsulation efficiency and yield were high, indicating that the method used is simple and efficient at this scale. The in-vitro release study showed no release in the acidic medium for 2?h followed by the release of the drug in pH 6.8 in case of Eudragit L100-55 and L100 and pH 7.4 in case of Eudragit S100. The pharmacokinetic parameters were calculated and method validation was performed to insure that it is suitable and reliable. Pharmacokinetic parameters were investigated by determining the C_max, T_max, AUC_0–t, K_el, and t_1/2 of the drug as a suspension and as microparticles. There was a significant difference (p?<?0.05) in T_max between the drug as a suspension and as microparticles. The effect of celecoxib on the degree of inflammation was examined on acetic acid induced colitis rat model and the drug was given as a suspension and as microparticles. The evaluation was done using macroscopical, microscopical and biochemical examination. There was a significant difference between the acetic acid control group and the treatment groups regarding all examination criteria in the order microparticles formulated using Eudragit S100 followed by Eudragit L100-55 while microparticles using Eudragit L100 and drug suspension showed almost the same results.     

Protein–polyelectrolyte interactions: Monitoring particle formation and growth by nanoparticle tracking analysis and flow imaging microscopy

The purpose of this study was to investigate the formation and growth kinetics of complexes of proteins and oppositely charged polyelectrolytes. Equal volumes of IgG and dextran sulfate (DS) solutions, 0.01 mg/ml each in 10 mM phosphate, pH 6.2, were mixed. At different time points, samples were taken and analyzed by nanoparticle tracking analysis (NTA), Micro-Flow Imaging (MFI) and size-exclusion chromatography (SEC). SEC showed a huge drop in monomer content (approximately 85%) already 2 min after mixing, while a very high nanoparticle (size up to 500 nm) concentration (ca. 9 × 10⁸/ml) was detected by NTA. The nanoparticle concentration gradually decreased over time, while the average particle size increased. After a lag time of about 1.5 h, a steady increase in microparticles was measured by MFI. The microparticle concentration kept increasing up to about 1.5 × 10⁶/ml until it started to slightly decrease after 10 h. The average size of the microparticles remained in the low-μm range (1–2 μm) with a slight increase and broadening of the size distribution in time. The experimental data could be fitted with Smoluchowski’s perikinetic coagulation model, which was validated by studying particle growth kinetics in IgG:DS mixtures of different concentrations. In conclusion, the combination of NTA and MFI provided novel insight into the kinetics and mechanism of protein–polyelectrolyte complex formation.     

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.     

Synthesis and study of controlled release of ofloxacin from polyester conjugates

This research compares the anti-tumor efficacy of paclitaxel delivered intratumorally in PLGA nanoparticles, microparticles, or the commercial Paclitaxel Injection^®. The hypothesis of the research is that larger PLGA microparticles adhere to mucus on the cell surface, release paclitaxel locally, and enhance cellular association of paclitaxel. PLGA-paclitaxel particles of mean diameters 315 nm, 1 μm, and 10 μm were prepared and their drug content, in vitro release, and cellular association of paclitaxel into 4T1 cells quantified. These particles were injected intratumorally into tumor xenografts, and the tumor volumes monitored over 13 days. Mean tumor volumes of the groups that received placebo and the 315 nm nanoparticles increased 2 and 1.5 times, respectively. Tumor growth was arrested in groups that received 1 μm and 10 μm microparticles. Additional cell culture studies were performed to test the hypothesis. The size-dependent increase in cellular concentration of paclitaxel was independent of duration of incubation of PLGA particles with 4T1 cells, and was enhanced 1.5 times by coating the particles or 4T1 cells with mucin. These particles were not internalized by clathrin-mediated endocytosis or macropinocytosis. In conclusion, PLGA microparticles sustained drug release, increased cellular concentration, and enhanced anti-tumor efficacy of paclitaxel compared to nanoparticles and Paclitaxel Injection^®.     

Encapsulation of poorly soluble basic drugs into enteric microparticles: a novel approach to enhance their oral bioavailability

Poorly water soluble basic drugs are very sensitive to pH changes and following dissolution in the acidic stomach environment tend to precipitate upon gastric emptying, which leads to compromised or erratic oral bioavailability. In this work, we show that the oral bioavailability of a model poorly soluble basic drug (cinnarizine) can be improved by drug encapsulation within highly pH-responsive microparticles (Eudragit L). The latter was prepared by emulsion solvent evaporation which yielded discrete spherical microparticles (diameter of 56.4 ± 6.8 μm and a span of 1.2 ± 0.3). These Eudragit L (dissolution threshold pH 6.0) microparticles are expected to dissolve and release their drug load at intestinal conditions. Thus, the enteric microparticles inhibited the in vitro release of drug under gastric conditions, despite high cinnarizine solubility in the acidic medium. At intestinal conditions, the particles dissolved rapidly and released the drug which precipitated out in the dissolution vessel. In contrast, cinnarizine powder showed rapid drug dissolution at low pH, followed by precipitation upon pH change. Oral dosing in rats resulted in a greater than double bioavailability of Eudragit L microparticles compared to the drug powder suspension, although C_max and T_max were similar. The higher bioavailability with microparticles contradicts the in vitro results. Such an example highlights that although in vitro results are an indispensable tool for formulation development, an early in vivo assessment of formulation behaviour can provide better prediction for oral bioavailability.     

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     

A novel coating concept for ileo-colonic drug targeting: Proof of concept in humans using scintigraphy

The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT® S neutralised to pH 8.0 and a buffer salt (10% KH₂PO₄), which was overcoated with layer of standard EUDRAGIT® S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT® S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1 N HCl for 2 h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1 N HCl for 2 h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120 min, while in contrast drug release from the double-coated tablets was initiated at 60 min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT® S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT® S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region.