[Preparation and in vitro evaluation of quercetin nanosuspension stabilized by gypenosides].

This study was designed to explore the potential of gypenosides as a novel natural stabilizer for the production of nanosuspensions. The gypenosides-stabilized quercetin nanosuspensions(QUE-NS) were prepared using the high-speed shearing and high-pressure homogenization method with quercetin as a model drug, followed by their in vitro evaluation.Based on the measured mean particle size and polydispersity index(PDI) of QUE-NS,the single factor experiment was conducted to optimize the preparation process parameters.The freeze-drying method was used to transform QUE-NS into freeze-dried powders, whose storage stability and saturation solubility were then studied.Moreover, the effects of pH and ionic strength on the physical stability of the nanosuspension system were examined.According to the results, the optimized process parameters were listed as follows: shear rate 13 000 r·min~(-1),shear time 2 min, homogenization pressure 100 MPa, and homogenization frequency 12 times.The mean particle size of QUE-NS prepared under the optimum process conditions was(461.9±2.4) nm, and the PDI was 0.059±0.016.During the two months of storage at room temperature, the freeze-dried QUE-NS powders remained stable.The saturation solubility of freeze-dried QUE-NS powders was proved higher than those of quercetin and the physical mixture.The results of stability testing demonstrated that QUE-NS stabilized with gypenosides exhibited good stability within the pH range of 6 to 8,while coalescence was prone to occur in the presence of salt.Overall, gypenosides is expected to become a new natural stabilizer for the preparation of nanosuspensions.

Comparison of media milling and microfluidization methods for engineering of nanocrystals: a case study.

OBJECTIVE: The article focuses on exploring and comparing two top-down methods, i.e. media milling and microfluidization for the fabrication of nanocrystals of rifampicin (RIF), a poorly water-soluble drug in terms of their potential for generation of stable and efficacious nanocrystals. SIGNIFICANCE: Nanocrystals are often the system of choice for the formulation of poorly water-soluble drugs. The characteristic benefit of nanocrystals lies in their ability to boost the bioavailability of such drugs by enhancing their saturation solubility and dissolution velocity. Nanocrystals can be prepared by either bottom-up or top-down approach. The latter is often preferred due to the feasibility of scale-up and economical nature. Hence, the emphasis is on these methods. METHODS: Stable RIF nanocrystals (RIF NCs) were developed and optimized using media milling and microfluidizer method by incorporating a suitable surfactant/stabilizer. The developed nanocrystals were evaluated for their saturation solubility, in vitro dissolution, solid-state characteristics, morphology, intrinsic dissolution rate, and short-term physical stability. RESULTS: Both the methods were found to be equally efficient in terms of development of stable RIF NCs, while in terms of processing time and efficacy, microfluidization was found to be advantageous. Amorphization and polymorphic conversion were evident based on the results of solid-state characterization. Furthermore, both formulations exhibited an enhanced solubility and faster dissolution velocity. CONCLUSION: Based on the characterization outcomes, it can be concluded that both the top-down technologies could be successfully applied to develop nanocrystals of poorly water-soluble drugs. However, microfluidization was found to outplay media milling in terms of processing time and drug loading.

Solidification of hesperidin nanosuspension by spray drying optimized by design of experiment (DoE).

OBJECTIVE: To accelerate the determination of optimal spray drying parameters, a "Design of Experiment" (DoE) software was applied to produce well redispersible hesperidin nanocrystals. SIGNIFICANCE: For final solid dosage forms, aqueous liquid nanosuspensions need to be solidified, whereas spray drying is a large-scale cost-effective industrial process. METHODS: A nanosuspension with 18% (w/w) of hesperidin stabilized by 1% (w/w) of poloxamer 188 was produced by wet bead milling. The sizes of original and redispersed spray-dried nanosuspensions were determined by laser diffractometry (LD) and photon correlation spectroscopy (PCS) and used as effect parameters. In addition, light microscopy was performed to judge the redispersion quality. RESULTS: After a two-step design of MODDE 9, screening model and response surface model (RSM), the inlet temperature of spray dryer and the concentration of protectant (polyvinylpyrrolidone, PVP K25) were identified as the most important factors affecting the redispersion of nanocrystals. As predicted in the RSM modeling, when 5% (w/w) of PVP K25 was added in an 18% (w/w) of hesperidin nanosuspension, subsequently spray-dried at an inlet temperature of 100 °C, well redispersed solid nanocrystals with an average particle size of 276 nm were obtained. By the use of PVP K25, the saturation solubility of the redispersed nanocrystals in water was improved to 86.81 µg/ml, about 2.5-fold of the original nanosuspension. In addition, the dissolution velocity was accelerated. CONCLUSIONS: This was attributed to the additional effects of steric stabilization on the nanocrystals and solubilization by the PVP polymer from spray drying.

Cefdinir nanosuspension for improved oral bioavailability by media milling technique: formulation, characterization and in vitro-in vivo evaluations.

Cefdinir (Cef) is an orally active Biopharmaceutics Classification System (BCS) class IV drug with incomplete absorption and low bioavailability (16-21%). The aim of this investigation was to develop nanosuspensions (NS) of Cef to improve its oral bioavailability. Cef NS were prepared by the media milling technique using zirconium oxide beads as the milling media. Cef NS were characterized by particle size, Scanning Electron Microscopy, Differential Scanning Calorimetry, X-Ray Diffraction pattern and evaluated for saturation solubility, in vitro release studies, ex vivo permeability studies and in vivo bioavailability studies. The particle size and zeta potential were found to be 224.2 ± 2.7 nm and -15.7 ± 1.9 mV, respectively. Saturation solubility of NS was found to be 1985.3 ± 10.2 µg/ml which was 5.64 times higher than pure drug (352.2 ± 6.5 µg/ml). The DSC thermograms and XRD patterns indicated that there was no interaction between drug and excipients and that the crystallinity of Cef remained unchanged after media milling process. Results of in vitro release studies and ex vivo permeation studies showed improved drug release of 88.2 1 ± 2.90 and 83.11 ± 2.14%, respectively, from NS after 24 h as compared to drug release of 54.09 ± 2.54 and 48.2 1 ± 1.27%, respectively, from the marketed suspension (Adcef). In vivo studies in rats demonstrated a 3-fold increase in oral bioavailability from the NS in comparison to marketed suspension. The results of this investigation conclusively show that the developed nanosuspension of Cef exhibited improved solubility, dissolution and permeation which led to a significant enhancement in its oral bioavailability.

Design, optimization and evaluation of glipizide solid self-nanoemulsifying drug delivery for enhanced solubility and dissolution.

A solid self-nanoemulsifying drug-delivery system (solid SNEDDS) has been explored to improve the solubility and dissolution profile of glipizide. SNEDDS preconcentrate was systematically optimized using a circumscribed central composite design by varying Captex 355 (Oil), Solutol HS15 (Surfactant) and Imwitor 988 (Co-surfactant). The optimized SNEDDS preconcentrate consisted of Captex 355 (30% w/w), Solutol HS15 (45% w/w) and Imwitor 988 (25% w/w). The saturation solubility (SS) of glipizide in optimized SNEDDS preconcentrate was found to be 45.12 ± 1.36 mg/ml, indicating an improvement (1367 times) of glipizide solubility as compared to its aqueous solubility (0.033 ± 0.0021 mg/ml). At 90% SS, glipizide was loaded to the optimized SNEDDS. In-vitro dilution of liquid SNEDDS resulted in a nanoemulsion with a mean droplet size of 29.4 nm. TEM studies of diluted liquid SNEDDS confirmed the uniform shape and size of the globules. The liquid SNEDDS was adsorbed onto calcium carbonate and talc to form solid SNEDDS. PXRD, DSC, and SEM results indicated that, the presence of glipizide as an amorphous and as a molecular dispersion state within solid SNEDDS. Glipizide dissolution improved significantly (p < 0.001) from the solid SNEDDS (∼100% in 15 min) as compared to the pure drug (18.37%) and commercial product (65.82) respectively.

Preparation of chitosan-coated hollow tin dioxide nanoparticles and their application in improving the oral bioavailability of febuxostat.

The aim of this study was to design a chitosan-coated hollow tin dioxide nanosphere (CS-HSn) for loading febuxostat (FEB) using an adsorption method to obtain a sustained-release system (CS-HSn-FEB) to improve the oral bioavailability of FEB. The morphological characteristics of hollow tin dioxide nanospheres (HSn) and CS-HSn were analyzed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The hemolysis test and CCK-8 test were used to assess the biosafety of HSn and CS-HSn. Powder X-ray diffraction (PXRD) and differential scanning thermal analysis (DSC) were performed on CS-HSn-FEB to analyze the drug presence status. The dissolution behavior and changes in plasma drug concentration of CS-HSn-FEB were evaluated in vitro and in vivo. Sections of intestinal tissues from SD rats were obtained to observe whether chitosan could increase the distribution of nanoparticles in the intestinal tissues. The results showed that FEB was present in CS-HSn in an amorphous state. Moreover, CS-HSn, with good biosafety, significantly improved the water solubility and oral absorption of FEB, indicating that CS-HSn has great potential to improve the intestinal absorption and oral bioavailability of insoluble drugs.

Feasibility of high melting point hydrochlorothiazide processing via cocrystal formation by hot melt extrusion paired fused filament fabrication as a 3D-printed cocrystal tablet.

The development of amorphous solid dispersions (ASDs) of high-melting-point drug substances using hot-melt extrusion (HME) continues to be challenging because of the limited availability of polymers that are stable at high processing temperatures. The main aim of this research project is to improve processability and develop three-dimensional (3D) cocrystal printlets of hydrochlorothiazide (HCTZ) using HME paired fused deposition modeling (FDM) techniques. Among the investigated coformers, nicotinamide (NIC) was identified as a suitable coformer. The cocrystal filaments of HCTZ-NIC and pure HCTZ that were suitable for the FDM 3D-printing process were developed using a Process 11 mm Twin -Screw Extruder with Kollicoat® IR and Kollidon® VA64 as polymeric carriers. The investigation of extruded filaments using differential scanning calorimetry (DSC) revealed the formation of HCTZ-NIC cocrystals, which was further confirmed using Fourier transform infrared spectroscopy (FTIR) and powder X-ray diffraction analysis (PXRD). The 3D-printed printlets of HCTZ-NIC with 50 % infill density resulted in improved dissolution and permeability compared to pure drug. This demonstrates the suitability of the HME-paired FDM 3D-printing technique for improving solubility and developing on-demand patient-focused dosage forms for poorly soluble high-melting-point drug substances by utilizing a cocrystal approach.

Antifungal nanosuspensions with surfactants and silver for the treatment of onychomycosis.

Fungal nail infection (Onychomycosis) often requires prolonged treatment and is associated with a high risk of resistance to treatment. Here in this contribution, we introduce a novel approach to enhance penetration and antifungal activity of the antifungal drug griseofulvin (GF). Solid dispersions were prepared with hydroxypropyl methylcellulose acetate succinate (HPMCAS) and combined with surfactant (either sodium dodecyl sulphate (SDS), dodecyl trimethylammonium bromide (DTAB), or Pluronic F127) using mechanochemical activation. The prepared powders were then suspended with spray-dried silica-coated silver nanoparticles and applied onto infected bovine hooves to assess permeability and antifungal activity. The results showed that the prepared nanosuspensions significantly suppressed fungal activity causing disruption of fungal biofilms. Raman mapping showed enhanced permeation while dynamic vapor sorption (DVS), and particle size measurements showed varied effects depending on the type of surfactant and milling conditions. The prepared nanosuspensions displayed enhanced solubility of the poorly soluble drug reaching approximately 1.2 mg/mL. The results showed that the dispersions that contained DTAB displayed maximum efficacy while the inclusion of colloidal silver did not seem to significantly improve the antifungal activity compared to other formulations.

Mechanochemical Synthesis and Physicochemical Characterization of Isoniazid and Pyrazinamide Co-crystals With Glutaric Acid.

The present work reports two novel pharmaceutical co-crystals; 2:1 isoniazid-glutaric acid (INHGA) and 2:1 pyrazinamide-glutaric acid (PGA). Isoniazid and pyrazinamide are key first-line drugs used for the treatment of tuberculosis. The co-crystals were produced via solid-state and solvent assisted grinding methods. Thermal characteristics of the samples were obtained using the differential scanning calorimetry, hot stage microscopy, and thermogravimetric analyses. The morphology of the powder samples by scanning electron microscopy, structural analysis by Fourier transform infrared spectroscopy and powder X-rays diffraction ensured co-crystal formation. Thermal analyses confirmed the co-crystals with new melting transitions ranging between their respective starting materials. Unique morphologies of the co-crystal particles were clear in SEM micrographs. The formation of intermolecular interactions with the co-crystal former was confirmed by the FT-IR spectral band shifting and was supported by distinct PXRD patterns of co-crystals thereby authenticating the successful co-crystal formation. In vitro solubility evaluation of the synthesized co-crystals by HPLC suggested a remarkable increase in solubility of both INH and PZA in their respective co-crystals.

Solubility Improvement of Progesterone from Solid Dispersions Prepared by Solvent Evaporation and Co-milling.

The aim of this contribution was to evaluate the impact of processing methods and polymeric carriers on the physicochemical properties of solid dispersions of the poorly soluble drug progesterone (PG). Five polymers: hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP) and silica (SiO2), and two processing methods: solvent evaporation (SE) and mechano-chemical activation by co-milling (BM) were applied. H-bonding was demonstrated by FTIR spectra as clear shifting of drug peaks at 1707 cm-1 (C20 carbonyl) and 1668 cm-1 (C3 carbonyl). Additionally, spectroscopic and thermal analysis revealed the presence of unstable PG II polymorphic form and a second heating DSC cycle, the presence of another polymorph possibly assigned to form III, but their influence on drug solubility was not apparent. Except for PG-MCC, solid dispersions improved drug solubility compared to physical mixtures. For SE dispersions, an inverse relationship was found between drug water solubility and drug-polymer Hansen solubility parameter difference (Δδt), whereas for BM dispersions, the solubility was influenced by both the intermolecular interactions and the polymer Tg. Solubility improvement with SE was demonstrated for all except PG-MCC dispersions, whereas improvement with BM was demonstrated by the PG-HPMC, PG-PVP and PG-HPMCAS dispersions, the last showing impressive increase from 34.21 to 82.13 µg/mL. The extensive H-bonding between PG and HPMCAS was proved by FTIR analysis of the dispersion in the liquid state. In conclusion, although SE improved drug solubility, BM gave more than twice greater improvement. This indicates that directly operating intermolecular forces are more efficient than the solvent mediated.

Griseofulvin solvate solid dispersions with synergistic effect against fungal biofilms.

Fungal biofilms are invariably recalcitrant to antifungal drugs and thus can cause recurrent serious infections. The aim of this work was to prepare highly effective form of the antifungal drug griseofulvin using the chloroform solvate embedded into different polymeric matrices. Based on their solid solubility, solvated (chloroform) and non-solvated (methanol and acetone) solid dispersions were prepared using different materials: silica, microcrystalline cellulose, polyvinylpyrrolidone and hydroxypropyl methylcellulose acetate succinate (HPMCAS) by which HPMCAS dispersions showed the highest solubility of about 200 µg/mL compared with ∼30 µg/mL for pure griseofulvin. The anti fungal potential of griseofulvin was assessed against the dermatophytes T. rubrum. Metabolic and protease activity of T. rubrum NCPF 935 with and without the presence of GF:HPMCAS chloroform solvates showed significant reduction compared to the untreated control after 24 h period. Confocal laser scanning microscopy showed thin hyphae compared to Control and GF:HPMCAS (non solvated). Dynamic vapour sorption data showed that HPMCAS formed most stable solvate structure preventing recrystallization and solvate expulsion, which could explain the disruptive effect of the biofilms. This could be explained by the formed hydrogen bonds as revealed by the solid and liquid state NMR data, which was further confirmed via thermal and FTIR analyses.

smartPearls - Novel physically stable amorphous delivery system for poorly soluble dermal actives.

Dermally applied poorly soluble actives whether in cosmetics or pharmaceuticals show insufficient skin penetration. Especially actives being insoluble in both phases of dermal vehicles, i.e. water and oil have no or less real effect. An approach to overcome this obstacle is the use of amorphous actives instead of the crystalline ones. The higher saturation solubility creates an increased concentration gradient between the formulation and skin. Thus, the diffusive flux into the skin is improved. However, the amorphous state of actives is highly labile, and the durability of such formulations would be too short for a marketable product. smartPearls is a novel technology efficiently long-term stabilize the amorphous state. They consist of µm sized particles with mesopores (e.g. silica: SYLOID®, AEROPERL®, Neusilin®), in which the active can be loaded and preserved in amorphous state. Due to the tightness of the pores, not enough space is given for re-crystallization. In this work, the skin penetration of poorly soluble actives loaded in smartPearls is compared to the present "gold standards" in dermal delivery, e.g. amorphous microparticles, amorphous nanoparticles and nanocrystals. The performance was at least similar or even better than the gold standards, explainable by the increased saturation solubility of active due to a) amorphous state and b) nanostructure inside the µm-sized particles. Sedimentation investigations showed, that the physical stabilization of very dense smartPearls in semi-solid vehicles is possible by viscoelastic repulsion. Also, the technical, regulatory and marketing aspects for the use of smartPearls technology in products are discussed, e.g. status of excipients used, and advantages of not being a nanoparticle, but being as efficient as them. Overall, smartPearls proved to be a promising dermal delivery technology for poorly soluble actives with a high market potential.

Preparation of amorphous indomethacin nanoparticles by aqueous wet bead milling and in situ measurement of their increased saturation solubility.

The aim of this study was to prepare amorphous indomethacin nanoparticles in aqueous media and to determine in situ their increased saturation solubility and dissolution rate. Drug nanosuspensions with a Z-average of ∼300 nm were prepared by wet media milling and afterwards freeze-dried. The drug solid state was analyzed by DSC, XRD and FTIR before and after the milling process. Milling of amorphous indomethacin with polyvinylpyrrolidone (PVP) as stabilizer resulted in an amorphous nanosuspension which could not be redispersed in the nanosize range after freeze-drying. The combination of PVP and poloxamer 407 resulted in crystalline nanoparticles: poloxamer 407, a polymer with high molecular weight, competed with PVP for surface coverage, and hindered the interaction between PVP and indomethacin. This indicated the importance of sufficient drug-PVP interactions on the drug particle surface for amorphous state stabilization. Redispersable amorphous indomethacin nanoparticles were obtained by combining the anti-recrystallization effect of PVP with the particle size stabilization provided by sodium dodecyl sulfate. Solubility studies were performed in situ. The solubility of crystalline micronized indomethacin of 6.7 ±â€¯1.3 µg/mL was increased up to 17.3 ±â€¯2.8 µg/mL by its amorphization, with a factor of increase of 2.6. Indomethacin amorphization increased its dissolution rate by a factor of 30. Indomethacin nanocrystals resulted in an increased solubility of 2.6 times, with a solubility of 17.2 ±â€¯0.4 µg/mL. The highest increase was obtained with amorphous indomethacin nanoparticles with a solubility of 35 ±â€¯1.6 µg/mL and 5.2 times higher than the solubility of the original indomethacin. Amorphous indomethacin nanoparticles resulted in the highest dissolution rate, which increased from 0.003 µg/(mL s) to 2.328 µg/(mL s). The synergistic effect obtained by the combination of nanosize and amorphous solid state was demonstrated.

Development and evaluation of wafer loaded with sertaconazole solid dispersion for the treatment of oral candidiasis

Abstract Candidiasis is one of the most common fungal infections of oral cavity in humans, causing great oral discomfort, pain and aversion to food. To develop more effective antifungal systems for the treatment of oral candidiasis, an oral mucoadhesive wafer containing sertaconazole solid dispersion (STZ-SD) was developed in this study. Dispersion of STZ in Soluplus® as a solubility enhancement excipient was done by melting, solvent evaporation and freeze drying method at various STZ to Soluplus® ratios. The optimized STZ-SD was then incorporated in the sodium carboxymethyl cellulose (SCMC) gel, xanthan gum gel, or their combination to prepare the lyophilized wafers. The swelling capacity, porosity, and mechanical, release and mucoadhesive properties of the wafers, together with their antifungal activity, were then evaluated. The melting method sample with the ratio of 8:1 showed the best results in terms of saturation solubility and dissolution rate. The STZ-SD-composite wafer exhibited higher hardness and mucoadhesion, as compared to those made of the SCMC polymer. The STZ-SD-wafer also exhibited a greater antifungal effect when compared to the STZ-wafer. The present study, thus, suggested that the STZ-SD-wafer could serve as a novel effective delivery system for oral candidiasis treatment.

Amorphous and Crystalline Particulates: Challenges and Perspectives in Drug Delivery.

Crystalline and amorphous dispersions have been the focus of academic and industrial research due to their potential role in formulating poorly water-soluble drugs. This review looks at the progress made starting with crystalline carriers in the form of eutectics moving towards more complex crystalline mixtures. It also covers using glassy polymers to maintain the drug as amorphous exhibiting higher energy and entropy. However, the amorphous form tends to recrystallize on storage, which limits the benefits of this approach. Specific interactions between the drug and the polymer may retard this spontaneous conversion of the amorphous drug. Some studies have shown that it is possible to maintain the drug in the amorphous form for extended periods of time. For the drug and the polymer to form a stable mixture they have to be miscible on a molecular basis. Another form of solid dispersions is pharmaceutical co-crystals, for which research has focused on understanding the chemistry, crystal engineering and physico-chemical properties. USFDA has issued a guidance in April 2013 suggesting that the co-crystals as a pharmaceutical product may be a reality; but just not yet! While some of the research is still oriented towards application of these carriers, understanding the mechanism by which drug-carrier miscibility occurs is also covered. Within this context is the use of thermodynamic models such as Flory-Huggins model with some examples of studies used to predict miscibility.

In situ determination of the saturation solubility of nanocrystals of poorly soluble drugs for dermal application.

The aim of this study was to determine, in situ, the saturation solubility and dissolution rate of nanocrystals of three poorly water-soluble drugs for dermal application. The nanocrystals were prepared by wet bead milling. Their size could be controlled by various process parameters. The saturation solubility was measured in water or in the presence of surfactant at 32°C with a Sirius® inForm based on in situ UV-vis spectroscopy. The saturation solubility of nanocrystals with sizes of ∼300nm increased for each drug in comparison to non-milled drug powders, with factors of increase in the range 1.3-2.8. The tacrolimus solubility was further analyzed with excess nanocrystal amounts four and ten times higher than the drug powder solubility. The corresponding solubility increases were 2.8 and 6.6 and thus dependent on the amount of excess nanocrystals. The higher increase was due to the presence of a larger fraction of small size particles, and only crystals far below 1µm showed supersaturation. The solubility increase for nanocrystals determined in situ was remarkably lower than the one previously reported with the use of non in situ methods. Nanomilling increased the drug dissolution rates: the highest increase was obtained with ibuprofen (rate increase ∼30).

Preparation and tableting of long-term stable amorphous rutin using porous silica.

Amorphous state of drugs increases the oral bioavailability, but typically faces physical stability problems. Amorphous rutin was generated and physically stabilized by encapsulating inside mesopores of porous AEROPERL® 300 Pharma and named as rutin CapsMorph® in this study. AEROPERL® 300 Pharma was loaded with rutin dissolved in DMSO containing Tween 80, and subsequently the solvent evaporated (wetness impregnation method). The loading process was monitored by light microscopy and scanning electron microscopy (SEM). X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to confirm the amorphous state in AEROPERL® 300 Pharma. A loading of 20% of the rutin-AEROPERL® 300 Pharma mixture was obtained. The amorphous state proved to be stable over 2years of storage at room temperature. Due to the amorphous state and the nanosize of the rutin in the mesopores, the kinetic saturation solubility increased to about 4mg/ml (water, 0.1MHCl, pH 6.8PBS) compared to the maximum observed thermodynamic equilibrium solubility of rutin raw drug powder of only 74.48±1.42µg/ml in pH 6.8PBS (=increase by factor about 54). The dissolution velocity also increased distinctly, e.g. about 96.1% of rutin dissolution from CapsMorph® powder in water within 5min compared to less than 40% of raw drug powder after 3h. Tablets were produced with rutin CapsMorph®, raw drug powder and their dissolution velocity compared to a marketed product. About 83.0-95.6% were released from the rutin CapsMorph® tablet within 5min, compared to 42.7-52.5% from the marketed tablet after 3h (water, 0.1MHCl, pH 6.8PBS). After dissolution the supersaturation level of rutin CapsMorph® remained over about 2h, then solubility slowly reduced, but remained after 48h still multifold above the thermodynamic rutin solubility. This should be sufficient for many poorly soluble drugs to achieve a sufficient bioavailability. For optimal exploitation of the supersaturation, a multiple step release system could be used, e.g. release of CapsMorph® particles every 2-3h.

Oral hesperidin-Amorphization and improved dissolution properties by controlled loading onto porous silica.

The oral bioavailability of poorly soluble drugs can be improved by amorphization generated by loading into the pores of mesoporous particles (pore size 2-50nm). The main mechanisms are increased kinetic saturation solubility and dissolution velocity due to the amorphous drug state and the nano-size of the drug (=increased dissolution pressure). In this study, the maximum achievable drug loading compared to the theoretical drug loading, and the effect of drug loading degree on the dissolution properties (solubility, dissolution velocity) were investigated. Hesperidin was used as the model active (having also practical relevance for e.g. nutraceutical products), loading was performed onto AEROPERL® 300 Pharma. Degree of successful drug loading could be easily followed by simple light microscopy (=useful tool for formulation optimization), and was in agreement with scanning electron microscopy. Amorphous versus crystalline state was followed by X-ray diffraction and differential scanning calorimetry. Loadings prepared were 28.6wt.%, 54.5wt.% and 60.0wt.%, the maximum theoretical loading was 72.5wt.%. Obviously the maximum drug loading is not achievable, the 54.5wt.% drug loading was the practical maximum with already some minor crystalline hesperidin on the surface. Interestingly, the maximum kinetic saturation solubility was obtained for the 54.5wt.% drug loading (941.74µg/ml in pH 6.8 PBS), versus 408.80µg/ml for the 60.0wt.% drug loading (=overloaded system). The raw drug powder had a thermodynamic solubility of only 18.40µg/ml. The fastest in vitro release was obtained with the 28.6wt.% loaded system, followed by the 54.5wt.% and 60.0wt.% loadings. The dissolution properties (solubility, dissolution velocity) can obviously be influenced by a "controlled loading". This is a simple, cost-effective technological alternative to modulating this property by chemical modification of silica, requiring a new costly regulatory approval of these chemically modified materials.

Development of surface stabilized candesartan cilexetil nanocrystals with enhanced dissolution rate, permeation rate across CaCo-2, and oral bioavailability.

Candesartan cilexetil (CC), an ester prodrug of candesartan, is BCS class II drug with extremely low aqueous solubility limiting its oral bioavailability. The present research aimed to develop a nanocrystalline formulation of CC with improved saturation solubility in gastrointestinal fluids and thereby, exhibiting enhanced oral bioavailability. CC nanocrystals were prepared using a low energy antisolvent precipitation methodology. A combination of hydroxypropyl methylcellulose (HPMC) and Pluronic® F 127 (50:50 w/w) was found to be optimum for the preparation of CC nanocrystals. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation was found to be 159 ± 8.1 nm, 0.177 ± 0.043, and -23.7 ± 1.02 mV, respectively. Optimized formulation was found to possess irregular, plate-like morphology as evaluated by scanning electron microscopy and crystalline as evaluated by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). A significant increase in saturation solubility and dissolution rate of the optimized nanosuspension was observed at all the tested pH conditions. Optimized CC nanocrystals exhibited a storage stability of more than 3 months when stored under cold and room temperature conditions. In vitro Caco-2 permeability further revealed that CC nanocrystals exhibited nearly 4-fold increase in permeation rate compared to the free CC. In vivo oral bioavailability studies of optimized CC nanocrystals in murine model revealed 3.8-fold increase in the oral bioavailability and twice the C max as compared with the free CC when administered orally. In conclusion, this study has established a crystalline nanosuspension formulation of CC with improved oral bioavailability in murine model. Graphical Abstract Antisolvent precipitation methodology for the preparation of Candesartan Cilexetil nanocrystals for enhanced solubility and oral bioavailability.

Formulation of dried lignans nanosuspension with high redispersibility to enhance stability, dissolution, and oral bioavailability.

Herpetospermum caudigerum lignans (HTL), one of the potential drugs with anti-hepatitis B virus and hepatoprotective effects, has limited clinical applications because of poor aqueous solubility and low bioavailability. Both herpetrione (HPE) and herpetin (HPN) are the most abundant ingredients in HTL and exhibit weak acidity. The purpose of the present study was to produce dried preparations of HTL (composed of HPE and HPN) nanosuspensions (HTL-NS) with high redispersibility using lyophilization technology. The HTL-NS was prepared by utilizing precipitation-combined homogenization technology based on acid-base neutralization reactions, and critical formulation and process parameters affecting the characteristics of HTL-NS were optimized. The resultant products were characterized by particle size analysis, SEM, XRD, stability, solubility, dissolution and in vivo bioavailability. HTL-NS showed near-spherical-shaped morphology and the size was 243 nm with a narrow PDI value of 0.187. The dried preparations with a relatively large particle size of 286 nm and a PDI of 0.215 were achieved by using 4% (W/V) mannitol as cryoprotectants, and had a better stability at 4 or 25 °C for 2 months, compared to HTL-NS. In the in vitro test, the dried preparations showed markedly increased solubility and dissolution velocity. Besides, in the in vivo evaluation, it exhibited significant increases in AUC0-t, Cmax,MRT and a decrease in Tmax, compared to the raw drug. In conclusion, our results provide a basis for the development of a drug delivery system for poorly water-soluble ingredients with pH-dependent solubility.