Combination of co-crystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs.

PURPOSE: Solubility and dissolution rate are essential for the oral absorption and bioavailability of poorly soluble drugs. The aim of this study was to prepare nano-co-crystals by combination of nanocrystal and co-crystal technologies, and investigate its effect, in situ, on increased kinetic solubility and dissolution rate. METHODS: Co-crystals of itraconazole-fumaric acid, itraconazole-succinic acid, indomethacin-saccharin and indomethacin-nicotinamide were prepared and nano-sized by wet milling. The particle size and solid state of the co-crystals were characterized by optical microscope, LD, PCS, DSC and XRPD before and after milling. RESULTS: 300-450 nm sized nano-co-crystals with a stable physical solid state were successfully prepared. Nano-co-crystals exhibited a lower crystallinity reduction than nanocrystals after wet milling. The particle size effect on the kinetic solubility of co-crystals was analysed for macro-, micro- and nano-co-crystals with in situ kinetic solubility studies. The maximum kinetic solubility of nano-co-crystals increased with excess conditions until a plateau. The highest increase was obtained with itraconazole-succinic acid nano-co-crystals with a kinetic solubility of 263.5 ± 3.9 µg/mL which was 51.5 and 6.6 times higher than the solubility of raw itraconazole and itraconazole-succinic acid co-crystal. CONCLUSIONS: The synergistic effect of nanocrystals and co-crystals with regard to increased kinetic solubility and dissolution rate was proven. The combination of the advantages of nanocrystals and co-crystals is a promising formulation strategy to increase both the solubility and dissolution rate of poorly soluble drugs.

Polymer type effect on PLGA-based microparticles preparation by solvent evaporation method with single emulsion system using focussed beam reflectance measurement.

AIM: This study aimed to investigate the effect of polymer type on solidification rate of PLGA polymeric microparticles and particle size/distribution of the emulsion droplets/hardened PLGA polymeric microparticles during solvent evaporation process using FBRM (Focussed Beam Reflectance Measurement). METHODS: PLGA polymeric microparticles were prepared by an O/W solvent evaporation method using various PLGA polymers, including PLGA Resomer® RG503H, RG502H and RG752H. The particle size mean, chord length distribution (CLD), and chord count of the emulsion droplets/hardened microparticles were monitored by FBRM. The morphology of polymeric microparticles were characterised by optical microscopy and scanning electron microscopy (SEM). RESULTS: The transformation of the emulsion droplets into solid microparticles occurred within the first 30 (± 1.04), 34 (± 1.15) and 37 (± 0.82) min and square weighted mean chord lengths are 64.08 (± 3.18), 52.36 (± 5.27) and 42.18 (± 4.61) µm when PLGA Resomer® RG503H, RG502H and RG752H were used respectively. Larger square weighted mean chord length of PLGA polymeric microparticles gave lower chord counts. PLGA RG752H microparticles gave smallest square weighted mean chord length and the chord counts was the highest. The CLDs measured by FBRM showed that a larger particle size mean gave longer CLD and a lower peak of particle number. SEM data revealed that the morphology of microparticles was influenced by type and physical properties of polymer. CONCLUSIONS: FBRM can be employed for online monitoring of the shift in the microparticle CLD and detect transformation of the emulsion droplets into solid microparticles during the solvent evaporation process. The microparticle CLD and transformation process were strongly influenced by polymer type.

Gel Strength of Hydrophilic Matrix Tablets in Terms of In Vitro Robustness.

PURPOSE: The purpose of this study was to correlate the gel strength of swollen matrix tablets with their in vitro robustness against agitation intensity and applied mechanical forces. Five commercial products, i.e. Glucophage®, Alfuzosin®, Tromphyllin®, Preductal® MR and Quetiapin® formulated as water-soluble/erodible matrix tablets were investigated. METHODS: Effect of agitation speed (50-150 rpm) on drug release, hydration/erosion and gel strength was investigated using USP paddle apparatus II. The gel strength of matrix tablets during dissolution at different conditions was characterized by a texture analyzer. RESULTS: Commercial tablets formulated with HPMC of higher viscosity, such as K15M or K100M, demonstrated the gel strength in swollen state >0.02 MPa. In this case, the release mechanism was predominantly diffusional and, therefore, not affected by stirring speed and mechanical stress. In contrast, the Quetiapin® matrix tablet, formulated with HPMC K 4 M in amount of approx. 25%, demonstrated the gel strength dropped below 0.02 MPa after 6 h of release. In this case, the drug was predominantly released via erosional mechanism and very susceptible to stirring speed. CONCLUSION: Sufficient gel strength of swollen tablets is an important prerequisite for unchanged in vitro performance in consideration of mechanical stress.

Evaluation of Hydrogenated Soybean Phosphatidylcholine Matrices Prepared by Hot Melt Extrusion for Oral Controlled Delivery of Water-Soluble Drugs.

The aims of this study were to prepare hydrogenated soybean phosphatidylcholine (HSPC) matrices by hot melt extrusion and to evaluate resulting matrix potential to extend drug release in regard to drug loading and solubility for oral drug delivery of water-soluble drugs. The liquid crystalline nature of HSPC powder allowed its extrusion at 120°C, which was below its capillary melting point. Model drugs with a wide range of water solubilities (8, 20 and 240 mg/mL) and melting temperatures (160-270°C) were used. Extrudates with up to 70% drug loading were prepared at temperatures below the drugs' melting points. The original crystalline state of the drugs remained unchanged through the process as confirmed by XRPD and hot-stage microscopy. The time to achieve 80% release (t80) from extrudates with 50% drug loading was 3, 8 and 18 h for diprophylline, caffeine and theophylline, respectively. The effect of matrix preparation method (extrusion vs. compression) on drug release was evaluated. For non-eroding formulations, the drug release retarding properties of the HSPC matrix were mostly not influenced by the preparation method. However, with increasing drug loadings, compressed tablets eroded significantly more than extruded matrices, resulting in 2 to 11 times faster drug release. There were no signs of erosion observed in extrudates with different drugs up to 70% loadings. The mechanical robustness of HSPC extrudates was attributed to the formation of a skin-core structure and was identified as the main reason for the drug release controlling potential of the HSPC matrices produced by hot melt extrusion.

Protein Corona Formation on Colloidal Polymeric Nanoparticles and Polymeric Nanogels: Impact on Cellular Uptake, Toxicity, Immunogenicity, and Drug Release Properties.

The adsorption of biomolecules to the surface of nanoparticles (NPs) following administration into biological environments is widely recognized. In particular, the "protein corona" is well understood in terms of formation kinetics and impact upon the biological interactions of NPs. Its presence is an essential consideration in the design of therapeutic NPs. In the present study, the protein coronas of six polymeric nanoparticles of prospective therapeutic use were investigated. These included three colloidal NPs-soft core-multishell (CMS) NPs, plus solid cationic Eudragit RS (EGRS), and anionic ethyl cellulose (EC) nanoparticles-and three nanogels (NGs)-thermoresponsive dendritic-polyglycerol (dPG) nanogels (NGs) and two amino-functionalized dPG-NGs. Following incubation with human plasma, protein coronas were characterized and their biological interactions compared with pristine NPs. All NPs demonstrated protein adsorption and increased hydrodynamic diameters, although the solid EGRS and EC NPs bound notably more protein than the other tested particles. Shifts toward moderately negative surface charges were also observed for all corona bearing NPs, despite varied zeta potentials in their pristine states. While the uptake and cellular adhesion of the colloidal NPs in primary human keratinocytes and human umbilical vein endothelial cells were significantly decreased when bearing the protein corona, no obvious impact was seen in the NGs. By contrast, corona bearing NGs induced marked increases in cytokine release from primary human macrophages not seen with corona bearing colloidal NPs. Despite this, no apparent enhancement to in vitro toxicity was noted. Finally, drug release from EGRS and EC NPs was assessed, where a decrease was seen in the EGRS NPs alone. Together these results provide a direct comparison of the physical and biological impact the protein corona has on NPs of widely varied character and in particular highlights a distinction between the corona's effects on NGs and colloidal NPs.

Micropellets coated with Kollicoat® Smartseal 30D for taste masking in liquid oral dosage forms.

The objective of this study was to develop delivery systems for taste masking based on multiparticulates coated with Kollicoat® Smartseal 30D formulated as liquid oral suspensions. Coating of particles containing bitter drugs with Kollicoat® Smartseal reduced drug leaching into aqueous medium, especially when increasing pH, therefore can be used for the formulation of liquid dosage forms. Application of an intermediate layer of ion exchange resins between drug layer and coating can further decrease drug leaching into aqueous vehicle that is beneficial in terms of taste masking. Using optimized compositions of liquid vehicles such as addition of sugar alcohols and ion exchange resin, reconstitutable or ready-to-use liquid dosage forms with micropellets can be developed with bitter taste protection after redispersion lasting longer than 3 weeks, which exceeds the usual period of application.

Influence of Drug Brittleness, Nanomilling Time, and Freeze-Drying on the Crystallinity of Poorly Water-Soluble Drugs and Its Implications for Solubility Enhancement.

The aim of this study was to assess whether wet bead milling of dexamethasone and tacrolimus suspensions leads to a lower degree of crystallinity of nanocrystals, and if the degree of crystallinity affects the drug solubility, in addition to particle size. Powder X-ray diffraction (XRD) was used to determine the degree of crystallinity of the particles, which decreased during milling until reaching a plateau: the particles had ∼79% degree of crystallinity after 5 h milling. Different milling times were required for the two drugs in order to reach their plateaux, 2 h for dexamethasone and 3 h for tacrolimus. These results could be explained with the brittleness of the drugs. Dexamethasone was more brittle than tacrolimus, with an apparent elastic modulus of 16 GPa compared to ∼12 GPa of tacrolimus. Freeze-drying the nanosuspensions resulted in a reduction in the degree of crystallinity to ∼35% for dexamethasone and to ∼45% for tacrolimus in comparison to non-freeze-dried particles. Solubility studies were performed with a Sirius® inForm based on in situ UV/VIS spectroscopy. The reduced degree of crystallinity of nanocrystals after milling was responsible, in addition to the nanoparticle size, for the solubility increase. Indeed, while the smallest particle size (394 nm for dexamethasone and 240 nm for tacrolimus) did not always result in the highest increase in solubility (factor of 1.04 for dexamethasone and 1.3 with tacrolimus), the smallest degree of crystallinity was always characteristic of the maximum solubility obtained (factor of 1.15 for dexamethasone and 1.7 for tacrolimus).

In situ forming implants for the delivery of metronidazole to periodontal pockets: formulation and drug release studies.

This study was performed to obtain prolonged drug release with biodegradable in situ forming implants for the local delivery of metronidazole to periodontal pockets. The effect of polymer type (capped and uncapped PLGA), solvent type (water-miscible and water-immiscible) and the polymer/drug ratio on in vitro drug release studies were investigated. In situ implants with sustained metronidazole release and low initial burst consisted of capped PLGA and N-methyl-2-pyrolidone as solvent. Mucoadhesive polymers were incorporated into the in situ implants in order to modify the properties of the delivery systems towards longer residence times in vivo. Addition of the polymers changed the adhesiveness and increased the viscosity and drug release of the formulations. However, sustained drug release over 10 days was achievable. Biodegradable in situ forming implants are therefore an attractive delivery system to achieve prolonged release of metronidazole at periodontal therapy.

Porous PLGA microparticles prepared with nanosized/micronized sugar particles as porogens.

The objective of this study was to explore the use of nanosized/micronized sugar particles as porogens for preparing porous poly(lactide-co-glycolide) (PLGA) microparticles by a solid-in-oil-in-water (S/O/W) solvent evaporation method. Porous PLGA microparticles containing dexamethasone were prepared with different nanosized/micronized sugars (sucrose, trehalose and lactose), types of PLGA, and osmogens (NaCl or sucrose) in the external water phase. The microparticles were characterized for morphology, thermal properties, particle size, surface area, encapsulation efficiency and drug release/swelling during release. The addition of nanosized/micronized sugar particles resulted in porous PLGA microparticles with high encapsulation efficiencies. The porosity of the microparticles was caused both by the influx of water into the polymer droplets and the encapsulation and subsequent dissolution of sugar particles during the manufacturing process. The porosity (pore size) of the microparticles and, as a result, the drug release pattern could be well controlled by the particle size and weight fraction of the sugar particles. Because of a larger inner surface area, nanosized sugar particles were more efficient porogen than micronized sugar particles to obtain porous PLGA microparticles with flexible release patterns.

Direct drug milling in organic PLGA solution facilitates the encapsulation of nanosized drug into PLGA microparticles.

The objective of this study was to prepare poly(lactide-co-glycolide) (PLGA) microparticles loaded with nanosized drug by combining non-aqueous wet bead milling and microencapsulation. 200-300 nm dexamethasone, hydrocortisone and dexamethasone sodium phosphate nanosuspensions were successfully prepared by wet bead milling the drug in dichloromethane using PLGA as a stabilizer. PLGA microparticles loaded with nanosized drugs were then prepared by a solid-in-oil-in-water (S/O/W) solvent evaporation method or solid-in-oil-in-oil (S/O/O) organic phase separation method. The microparticles were characterized by laser diffraction (LD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and in vitro drug release. The nanosized drugs were homogeneously distributed within the microparticle matrix and remained crystalline, however, with a decrease in crystallinity. High drug encapsulation efficiencies >80 % were achieved at theoretical drug loadings between 5 and 30 %. Drug release profiles could be controlled by varying PLGA grades/blends, microparticle size and drug loadings. Quasi-linear release profiles without the PLGA-typical slow release phase were achieved with PLGA encapsulated nanosized drug.

Effect of polymer molecular weight and of polymer blends on the properties of rapidly gelling nasal inserts.

The objective was to investigate the potential of polymer molecular weight (MW) and polymer blends for the control of drug release from in situ gelling nasal inserts prepared by lyophilization of solutions of model drugs (oxymetazoline HCl, diprophyllin) and polymers. Drug release, polymer solution viscosity, water uptake and mass loss, mechanical properties, and bioadhesion potential were measured. Sonication was effective to reduce the viscosity/polymer MW of carrageenan solutions. Nasal inserts prepared from sonicated carrageenan showed an insignificant reduction in water uptake with sonication time and no disintegration of the gel matrix. In contrast, inserts of different MW Na-alginates revealed a reduced water uptake and an increased mass loss with lower MW. Inserts prepared from carrageenan/low MW Na-alginate blends took up more water at a higher low MW Na-alginate content. Sonicated carrageenan inserts released oxymetazoline HCl independent of the sonication time and diprophyllin with only a slight reduction in the release rate. Release of both drugs from Na-alginate inserts was slow from high MW inserts because no insert dissolution occurred. Increasing the Na-alginate content of inserts prepared from polymer blends accelerated the drug release enabling release rates over a broad range. The bioadhesion potential of Na-alginate inserts was strongly reduced for the low MW grades because of dissolution of the inserts. Xanthan gum and Carbopol 971 blended with Na-alginate formed inserts with poor bioadhesion. The use of polymer blends to control the drug release from nasal inserts was superior to the use of polymers of different MW.

Reduction in burst release after coating poly(D,L-lactide-co-glycolide) (PLGA) microparticles with a drug-free PLGA layer.

The high initial burst release of a highly water-soluble drug from poly (D,L-lactide-co-glycolide) (PLGA) microparticles prepared by the multiple emulsion (w/o/w) solvent extraction/evaporation method was reduced by coating with an additional polymeric PLGA layer. Coating with high encapsulation efficiency was performed by dispersing the core microparticles in peanut oil and subsequently in an organic polymer solution, followed by emulsification in the aqueous solution. Hardening of an additional polymeric layer occurred by oil/solvent extraction. Peanut oil was used to cover the surface of core microparticles and, therefore, reduced or prevented the rapid erosion of core microparticles surface. A low initial burst was obtained, accompanied by high encapsulation efficiency and continuous sustained release over several weeks. Reduction in burst release after coating was independent of the amount of oil. Either freshly prepared (wet) or dried (dry) core microparticles were used. A significant initial burst was reduced when ethyl acetate was used as a solvent instead of methylene chloride for polymer coating. Multiparticle encapsulation within the polymeric layer increased as the size of the core microparticles decreased (< 50 µm), resulting in lowest the initial burst. The initial burst could be controlled well by the coating level, which could be varied by varying the amount of polymer solution, used for coating.

A comparative study of PLGA microparticle properties loaded with micronized, nanosized or dissolved drug.

The objective of this study was to compare properties of poly(lactide-co-glycolide) (PLGA) microparticles loaded with dexamethasone or hydrocortisone in the micronized, nanosized or dissolved state. Dexamethasone and hydrocortisone were nanosized by wet bead milling. The microparticles were prepared by a solvent extraction/evaporation method and were characterized by particle size, encapsulation efficiency, drug solid-state, morphology, in vitro release and dynamic microparticle diameter changes during release. The micronized and nanosized drugs were still in crystalline form after encapsulation into PLGA microparticles with encapsulation efficiencies greater than 85 %. Encapsulating dissolved drugs resulted in lower encapsulation efficiencies (32 to 63 %) and the dissolved drug recrystallized within the PLGA matrix at a higher actual drug loading of 30 %. The order in drug release depended on the physical state of the encapsulated drug and was in the order of dissolved > nanosized > micronized drug. Interestingly, quasi-linear release profiles were obtained with 10 % nanosized dexamethasone in PLGA 502H and 503H microparticles. In conclusion, encapsulating dispersed and, in particular, nanosized drug into PLGA microparticles is a promising tool to increase the encapsulation efficiency, to maintain a stable drug solid-state and to achieve a more continuous release profile.

Incorporation of itraconazole nano-co-crystals into multiparticulate oral dosage forms.

Limited research has been performed on the downstream processing of nano-co-crystal suspensions into solid oral dosage forms. The objectives of this study were to evaluate the impact of three downstream processes (wet granulation, spray granulation and bead layering) on the performance of itraconazole-succinic acid (ITZ-SUC) nano-co-crystal suspension. An optimized ITZ-SUC nano-co-crystal suspension mixed with HPMC E5 was utilized for the downstream processing. The suspension was converted in the solid state either by wet or spray granulation (with microcrystalline cellulose or lactose as substrates) or by layering onto microcrystalline cellulose and sugar beads. The multiparticulate solid dosage forms were characterized by optical microscopy, differential scanning calorimeter (DSC), X-ray powder diffraction (XRPD) and in situ dissolution studies. Spray granulation and bead layering resulted in less particle aggregation, a faster dissolution rate, and higher kinetic solubility when compared to wet granulation. ITZ-SUC nano-co-crystals spray granulated with lactose resulted in higher kinetic solubility profiles compared to microcrystalline cellulose granules. The type of bead core had no impact on the dissolution behavior. A slower dissolution and decreased kinetic solubility were observed with increasing drug loading for sprayed granules when microcrystalline cellulose was used as substrate. All dosage forms were stable under accelerated storage conditions (40 °C/75% RH) when blistered. Nano-co-crystals incorporated in granules were less stable than layered beads under non-blistered condition. Nano-co-crystals layered sugar beads are an interesting alternative to amorphous solid dispersion; a comparable kinetic solubility but a faster drug release were achieved. This study identified bead layering as a superior downstream process approach for incorporating ITZ-SUC nano-co-crystals into an oral solid dosage form without compromising drug dissolution.

Impact of dispersion time interval and particle size on release profiles of propranolol HCl and carbamazepines from microparticle blends system.

The objective of this study was to investigate the effect of dispersion time interval (DTI) on physicochemical properties of drug following the incorporation of propranolol HCl (Pro) and carbamazepine (CBZ) within ethyl cellulose (EC) microparticle blends using solvent evaporation method. The first Pro emulsion and second CBZ oil phase were dispersed in an external aqueous phase, with DTI of 0 and 60 min. The morphology of microparticle blends were characterized by SEM. The particle size mean of the emulsion droplets/hardened microparticles were monitored by FBRM. Encapsulation efficiency (EE) and in vitro drug release were also investigated. The resulting microparticle blends were spherical and formed two populations. The particle size mean of microparticle blends ranged from 113.27 µm to 122.42 µm. The EE was 77.28% to 78.64% for Pro and 96.48% to 98.64% for CBZ. FBRM studies showed that the size of microparticle blend prepared as W/O/W (Pro) and O/W (CBZ) system with DTI of 60 min and stirring time 4 h were larger than those prepared with DTI of 0 min. In vitro drug release studies after 28 days that revealed the CBZ release (58.72%) was faster than Pro release (43.16%). Investigation on surface morphology by SEM showed that the second drug CBZ which added as the oil phase in the W/O/W emulsion system had blocked the pores on the surface Pro microparticles prepared from the first primary emulsion, therefore affecting the drug release. This blocking effects of second drug (CBZ) on first emulsion microparticles (Pro) depended on the DTI. This phenomenon is only applicable if the first primary emulsion is W/O/W system.

Kinetic solubility improvement and influence of polymers on controlled supersaturation of itraconazole-succinic acid nano-co-crystals.

Nano-co-crystals enhance the solubility and dissolution rate of poorly soluble drugs. The objective of this study was to obtain a better understanding of the dissolution process of nano-co-crystals and of the precipitation inhibition by various polymers. Itraconazole-succinic acid (ITZ-SUC) nano-co-crystal was chosen as model drug formulation to investigate the supersaturation and precipitation inhibition capabilities of various polymers (HPMC E5, HPMC E50, HPMCAS, HPC-SSL, PVPK30 and PVPVA64). The kinetic concentration-time profiles of nano-co-crystal were measured under non-sink conditions with in situ UV-VIS spectroscopy. HPMC E5 performed best by achieving the greatest extended supersaturation/precipitation inhibition. The precipitation inhibition capacity of HPMC E5 was proportional to its concentration. The maximum achievable supersaturation was proportional to the dissolution rate which can be modulated by the rate of supersaturation generation (i.e., addition rate or dose). Supersaturation could be prolonged significantly resulting in 2-5-fold increased area under the dissolution curves compared to nano-co-crystals alone. This effect was limited by a critical excess of undissolved particles with high specific surface area which acted as crystallization seeds resulting in faster precipitation. The study highlighted that a faster dissolution rate and the use of precipitation inhibitors were two key factors determining the extent and time of supersaturation of nano-co-crystals.

Real-time particle size analysis using focused beam reflectance measurement as a process analytical technology tool for continuous microencapsulation process.

The online real-time particle size analysis of the microencapsules manufacturing process using the continuous solvent evaporation method was performed using focused beam reflectance measurement (FBRM). In this paper, we use FBRM measurements to investigate the effects of polymer type and compare the size distributions to those obtained using other sizing methods such as optical microscope and laser diffraction. FBRM was also utilized to measure the length-weighted chord length distribution (CLD) and particle size distribution (PSD) online during particle solidification, which could not be done with laser diffraction or nested sieve analysis. The chord lengths and CLD data were taken at specific times using an online FBRM probe mounted below the microparticle. The timing of the FBRM determinations was coordinated with the selection of microparticle samples for particle size analysis by optical microscope and laser diffraction calculation as a reference. For all three produced batches tested, FBRM, laser diffraction, and sieve analysis yielded similar results. Hardening time for the transformation of emulsion droplets into solid microparticles occurred within the first 10.5, 19, 25, 30, and 55 min, according to FBRM results. The FBRM CLDs revealed that a larger particle size mean resulted in a longer CLD and a lower peak of particle number. The FBRM data revealed that the polymer type had a significant impact on microparticle CLD and the transformation process.

Improved lysozyme stability and release properties of poly(lactide-co-glycolide) implants prepared by hot-melt extrusion.

PURPOSE: To assess the feasibility of hot-melt extrusion (HME) for preparing implants based on protein/poly(lactide-co-glycolide) (PLGA) formulations with special emphasis on protein stability, burst release and release completeness. METHOD: Model protein (lysozyme)-loaded PLGA implants were prepared with a screw extruder and a self-built syringe-die device as a rapid screening tool for HME formulation optimization. Lysozyme stability was determined using DSC, FTIR, HPLC and biological activity. The simultaneous effect of lysozyme and PEG loadings was investigated to obtain optimized formulations with high drug loading but low initial release. RESULTS: Lysozyme was recovered from implants with full biological activity after HME. The release from all implants reached the 100% value in 60-80 days with nearly complete enzymatic activity of the last fraction of released lysozyme. Pure PLGA implants with up to 20% lysozyme loading could be formulated without initial burst. The incorporation of PEG 400 reduced the initial burst at drug loadings in excess of 20%. CONCLUSION: A complete lysozyme recovery in active form with a burst-free and complete release from PLGA implants prepared by hot-melt extrusion was obtained. This is in contrast to many reported microparticulate lysozyme-PLGA systems and suggests the great potential of hot-melt extrusion for the preparation of protein-PLGA implants.

Effect of water-soluble polymers on the physical stability of aqueous polymeric dispersions and their implications on the drug release from coated pellets.

PURPOSE: To investigate the physical stability and drug release-related properties of the aqueous polymer dispersions Kollicoat((R)) SR 30 D and Aquacoat((R)) ECD (an ethylcellulose-based dispersion) in the presence water-soluble polymers (pore formers) with special attention to the potential flocculation of the polymer dispersions. METHODS: A precise characterization of the flocculation phenomena in undiluted samples was monitored with turbidimetric measurements using the Turbiscan Lab-Expert. Theophylline or propranolol HCl drug-layered pellets were coated with Kollicoat((R)) SR 30 D and Aquacoat((R)) ECD by the addition of water-soluble polymers polyvinyl pyrrolidone (Kollidon((R)) 30 and 90 F), polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat((R)) IR), and hydroxypropyl methylcellulose (Pharmacoat((R)) 603 or 606) in a fluidized bed coater Glatt GPCG-1 and drug release was performed according to UPS paddle method. RESULTS: Stable dispersions were obtained with both Kollicoat((R)) SR 30 D (a polyvinyl acetate-based dispersion) and Aquacoat((R)) ECD with up to 50% hydrophilic pore formers polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat((R)) IR) and polyvinyl pyrrolidone (Kollidon((R)) 30). In general, Kollicoat((R)) SR 30 D was more stable against flocculation than Aquacoat((R)) ECD. Stable dispersions were also obtained with higher amounts of water-soluble polymer or by reducing the concentration of the polymer dispersion. Flocculated dispersions resulted in porous films and, thus, in a sharp increase in drug release. CONCLUSIONS: Kollicoat((R)) SR 30 D was more resistant to flocculation upon addition of water-soluble polymers than Aquacoat((R)) ECD. The continuous adjustment of drug release from Kollicoat((R)) SR 30-coated pellets was possible with Kollicoat((R)) IR amounts over a broad range.

In situ gelling nasal inserts for influenza vaccine delivery.

PURPOSE: The objective of this study was to investigate the potential of rapidly gelling nasal inserts as vaccine delivery system. METHODS: Nasal inserts were prepared by freeze-drying hydrophilic polymer solutions containing influenza split vaccine. In vitro vaccine release from polymer solutions and inserts and the vaccine hemagglutination activity were determined. In vivo immunization studies in mice and rats were performed with nasal solutions and nasal inserts. RESULTS: The in vitro release of proteins (vaccine) from polymeric solutions and inserts was incomplete because of the high molecular weight of the proteins. The release rate was controlled by the polymer (Lutrol F68 > PVP 90 > HPMC K15M > Carbopol > chitosan > or = carrageenan = xanthan gum) because of differences in solution viscosity and possible polymer-protein interactions. Xanthan gum, a negatively charged polymer with intrinsic adjuvanticity, enhanced the serum IgG as well as the nasal IgA response in in vivo studies with nasal vaccine solutions. Poly-l-arginine and cationic lipid were the best performing adjuvants. Solutions containing vaccine with xanthan gum and cationic lipid were effectively stabilized with 0.4 M NaCl. DISCUSSION: The specific activity of the major vaccine protein, hemagglutinin, was not significantly affected by the addition of polymers and the freeze-drying process during insert preparation. The addition of cationic lipid as adjuvant decreased the hemagglutination activity, which strongly indicated inhibition of the protein binding site to erythrocytes. Inserts prepared from xanthan gum and cationic lipid stabilized with NaCl showed a reduced protein activity but were superior to the cationic lipid alone. CONCLUSION: Rat immunization with solid nasal inserts based on xanthan gum containing the influenza vaccine, with or without an additional cationic lipid adjuvant, resulted in similar IgG levels as the pure nasal liquid vaccine formulation.