Affinity-based growth factor delivery using biodegradable, photocrosslinked heparin-alginate hydrogels

Photocrosslinkable biomaterials are promising for tissue engineering applications due to their capacity to be injected and form hydrogels in situ in a minimally invasive manner. Our group recently reported on the development of photocrosslinked alginate hydrogels with controlled biodegradation rates, mechanical properties, and cell adhesive properties. In this study, we present an affinity-based growth factor delivery system by incorporating heparin into photocrosslinkable alginate hydrogels (HP-ALG), which allows for controlled, prolonged release of therapeutic proteins. Heparin modification had minimal effect on the biodegradation profiles, swelling ratios, and elastic moduli of the hydrogels in media. The release profiles of growth factors from this affinity-based platform were sustained for 3 weeks with no initial burst release, and the released growth factors retained their biological activity. Implantation of bone morphogenetic protein-2 (BMP-2)-loaded photocrosslinked alginate hydrogels induced moderate bone formation around the implant periphery. Importantly, BMP-2-loaded photocrosslinked HP-ALG hydrogels induced significantly more osteogenesis than BMP-2-loaded photocrosslinked unmodified alginate hydrogels, with 1.9-fold greater peripheral bone formation and 1.3-fold greater calcium content in the BMP-2-loaded photocrosslinked HP-ALG hydrogels compared to the BMP-2-loaded photocrosslinked unmodified alginate hydrogels after 8 weeks implantation. This sustained and controllable growth factor delivery system, with independently controllable physical and cell adhesive properties, may provide a powerful modality for a variety of therapeutic applications.     

Multilayered composite-coated ionically crosslinked food-grade hydrogel beads generated from algal alginate for controlled and sustained release of bioactive compounds

Hydrogels have gained interest as sustained-release matrices partly because of their high biocompatibility and ease of preparation. Their wide application has, however, been limited by their poor mechanical strength and their lack of tunability in the performance of bioactive agent delivery. By using the lake substratum as a gel property modifier, in combination with the use of the surface coating approach and the ionic gelation technique, hydrogel beads are generated from algal alginate for controlled and sustained release of bioactive compounds. Both the acute and chronic toxicity of the beads are found to be negligible in 3T3 fibroblasts. The capacity of the beads in retaining the activity of the loaded agent is verified by the negligible change in the action of the loaded compound on foodborne bacteria (viz., Staphylococcus aureus and Escherichia coli). Along with the high flexibility provided by the adopted method in the choice of coating materials, our beads extend the limitations of conventional ionically crosslinked gel systems, and show high potential for applications in functional food development, nutraceutical delivery, and pharmaceutical formulation.

Multilayered composite-coated hydrogel beads are generated from algal alginate as carriers of bioactive compounds. They show high potential for applications in functional food development, nutraceutical delivery, and pharmaceutical formulation.     

Oral colon-specific drug delivery for bee venom peptide: development of a coated calcium alginate gel beads-entrapped liposome.

Colon-specific drug delivery systems (CDDSs) can be used to improve the bioavailability of protein and peptide drugs through the oral route. A novel formulation for oral administration using coated calcium alginate gel beads-entrapped liposome and bee venom peptide as a model drug has been investigated for colon-specific drug delivery in vitro. Drug release studies under conditions mimicking stomach to colon transit have shown that the drug was protected from being released completely in the physiological environment of the stomach and small intestine. The release rate of bee venom from the coated calcium alginate gel beads-entrapped liposome was dependent on the concentration of calcium and sodium alginate, the amount of bee venom in the liposome, as well as the coating. Furthermore, a human gamma-scintigraphy technique was used in vivo to determine drug delivery more precisely. The colonic arrival time of the tablets was found to be 4-5 h. The results clearly demonstrated that the coated calcium alginate gel beads-entrapped liposome is a potential system for colon-specific drug delivery.     

Oral sustained delivery of theophylline using in-situ gelation of sodium alginate.

Gels formed in situ following oral administration of aqueous solutions of sodium alginate (1.0-2.0%w/v) to rats were evaluated as sustained release vehicles for the delivery of theophylline. The liquid formulation contained calcium ions in complexed form, the release of which in the acidic environment of the stomach caused gelation of the alginate. Bioavailability of theophylline from alginate gels formed by in situ gelation in the rat stomach was increased by 1.3-2-fold in rats for alginate concentrations of 2.0 to 1.0%w/v respectively compared with that from a proprietary oral sustained release formulation containing an identical drug concentration. There was no significant difference in the mean residence times of theophylline when administered by these two vehicles.     

Alginate-based oral drug delivery system for tuberculosis: pharmacokinetics and therapeutic effects

Alginate microparticles were developed as oral sustained delivery carriers for antitubercular drugs in order to improve patient compliance. In the present study, pharmacokinetics and therapeutic effects of alginate microparticle encapsulated antitubercular drugs, i.e. isoniazid, rifampicin and pyrazinamide were examined in guinea pigs. Alginate microparticles containing antitubercular drugs were evaluated for in vitro and in vivo release profiles. These microparticles exhibited sustained release of isoniazid, rifampicin and pyrazinamide for 3-5 days in plasma and up to 9 days in organs. Peak plasma concentration (Cmax), Tmax, elimination half-life (t1/2e) and AUC0- infinity of alginate drugs were significantly higher than those of free drugs. The encapsulation of drug in alginate microparticles resulted in up to a nine-fold increase in relative bioavailability compared with free drugs. Chemotherapeutic efficacy of alginate drug microspheres against experimental tuberculosis showed no detectable cfu values at 1:100 and 1:1000 dilutions of spleen and lung homogenates. Histopathological studies further substantiated these observations, thus suggesting that application of alginate-encapsulated drugs could be useful in the effective treatment of tuberculosis.     

Vaginal delivery of siRNA using a novel PEGylated lipoplex-entrapped alginate scaffold system

Sustained vaginal delivery of siRNA has been precluded by the mucosal barrier lining the vaginal tract. In contrast to prior reports, we showed that conventional lipoplexes administered intravaginally are unable to reach the vaginal epithelium under normal physiological conditions. Here we have developed a novel alginate scaffold system containing muco-inert PEGylated lipoplexes to provide a sustained vaginal presence of lipoplexes in vivo and to facilitate the delivery of siRNA/oligonucleotides into the vaginal epithelium. These PEGylated lipoplex-entrapped alginate scaffolds (PLAS) were fabricated using a freeze-drying method and the entrapment efficiency, release rate, and efficacy were characterized. We demonstrated that the PLAS system had an entrapment efficiency of ~ 50%, which released PEGylated lipoplexes gradually both in vitro and in vivo. While the presence of alginate diminished the cell uptake efficiency of PEGylated lipoplexes in vitro, as expected, we showed a six-fold increase their uptake into the vaginal epithelium compared to existing transfection systems following intravaginal administration in mice. A significant knockdown of Lamin A/C level was also observed in vaginal tissues using siLamin A/C-containing PLAS system in vivo. Overall, our results indicated the potential of the biodegradable PLAS system for the sustained delivery of siRNA/oligonucleotides to vaginal epithelium.     

Enzymatically cross-linked injectable alginate-g-pyrrole hydrogels for neovascularization

Microparticles capable of releasing protein drugs are often incorporated into injectable hydrogels to minimize their displacement at an implantation site, reduce initial drug burst, and further control drug release rates over a broader range. However, there is still a need to develop methods for releasing drug molecules over extended periods of time, in order to sustain the bioactivity of drug molecules at an implantation site. In this study, we hypothesized that a hydrogel formed through the cross-linking of pyrrole units linked to a hydrophilic polymer would release protein drugs in a more sustained manner, because of an enhanced association between cross-linked pyrrole groups and the drug molecules. To examine this hypothesis, we prepared hydrogels of alginate substituted with pyrrole groups, alginate-g-pyrrole, through a horse-radish peroxidase (HRP)-activated cross-linking of the pyrrole groups. The hydrogels were encapsulated with poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with vascular endothelial growth factor (VEGF). The resulting hydrogel system released VEGF in a more sustained manner than Ca^2 + alginate or Ca^2 + alginate-g-pyrrole gel systems. Finally, implantations of the VEGF-releasing HRP-activated alginate-g-pyrrole hydrogel system on chicken chorioallantoic membranes resulted in the formation of blood vessels in higher densities and with larger diameters, compared to other control conditions. Overall, the drug releasing system developed in this study will be broadly useful for regulating release rates of a wide array of protein drugs, and further enhance the quality of protein drug-based therapies.     

MMP-responsive in situ forming hydrogel loaded with doxorubicin-encapsulated biodegradable micelles for local chemotherapy of oral squamous cell carcinoma

The complex construction within the oral cavity causes incomplete surgical resection of oral squamous cell carcinoma (OSCC) that may enhance the risk of recurrence and metastasis in the treatment. In situ forming injectable hydrogels with minimally invasive procedures, encapsulation stability and stimuli-responsive degradation have emerged as promising carriers for local drug delivery. In this study, doxorubicin (DOX) was first encapsulated in biodegradable poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA) micelles and then loaded into an in situ injectable hyaluronic acid (HA) hydrogel, which was cross-linked by a matrix metalloproteinase-2 (MMP-2)-responsive peptide (GCRDGPQGIWGQDRCG) through a Michael addition reaction. In vitro studies demonstrated that the HA hydrogel had a sensitive MMP-2-responsive drug release profile. Investigations including MTT, live-dead, apoptosis, and wound healing assays illustrated that DOX micelle-loaded HA hydrogels exhibited outstanding cytotoxicity against squamous carcinoma cells (SCC-15). Furthermore, by in vivo studies, we also proved that HA hydrogels degraded faster in the tumor site than in normal tissue, which led to a local sustained release of DOX-loaded micelles and tumor growth inhibition of oral squamous cell carcinoma (OSCC) without any damage to the organs. Therefore, this work provides a remarkable drug delivery platform for local chemotherapy and other applications.

The complex construction within the oral cavity causes incomplete surgical resection of oral squamous cell carcinoma (OSCC) that may enhance the risk of recurrence and metastasis in the treatment.     

In vitro and in vivo evaluation of starch-based hot stage extruded double matrix systems.

The objective of developing a double matrix system consisting of a hot stage extruded starch pipe surrounding a hot stage extruded and drug-containing starch core, was to obtain a monolithic matrix system applicable in the domain of sustained drug release. The behaviour of the systems was evaluated through dissolution testing and through a randomised crossover bioavailability study on nine male volunteers. All double matrix systems showed in vitro a nearly constant drug release profile after an initial slower release phase of 4 h. This initial slower release phase was avoided by loading the starch pipe with a small amount of drug. The in vitro dissolution profiles did not reflect the in vivo behaviour of the systems. Although the in vitro dissolution profiles of two selected double matrix systems were slower than the profile of a commercially available sustained release formulation, they performed less well in vivo. However, the t75%Cmax ratios of the evaluated double matrix systems versus a reference immediate release formulation indicated an acceptable sustained release behaviour, superior to that of hot stage extruded starch-based single matrices. Therefore the disclosed drug delivery systems could be applied in the domain of sustained drug delivery. Besides, the continuous production of the double matrix systems offers an advantage from a manufacturing point of view.     

Sustained delivery of anti-VEGF from injectable hydrogel systems provides a prolonged decrease of endothelial cell proliferation and angiogenesis in vitro

Therapeutic antibodies are attractive treatment options for numerous diseases based on their ability to target and bind to specific proteins or antigens. Bevacizumab, an antiangiogenic antibody, has shown promise for multiple diseases, including various cancers and macular degeneration, where excessive VEGF secretion induces aberrant angiogenesis. In many cases local, sustained delivery of a therapeutic antibody would be preferable to maximize the therapeutic at the disease site, eliminate the need for repeated doses, and reduce systemic side effects. The biodegradable polysaccharides alginate and chitosan can electrostatically interact to form a polyelectrolyte complex (PEC), and have proved effective as a carrier for controlled release of antibodies. In this work, an alginate–chitosan PEC system was designed to produce targeted 30-day delivery of non-specific IgG and anti-VEGF antibodies. The release of anti-VEGF was slow relative to IgG release, suggesting that release rate is antibody specific and is based on the interactions of the PEC with charges present on the antibody surface. The anti-VEGF released from the PEC was shown to successfully inhibit VEGF-induced proliferation and angiogenesis in vitro throughout the 30-day test period.

Sustained delivery of bioactive anti-VEGF antibodies is demonstrated using a polyelectrolyte complex of alginate and chitosan. The released anti-VEGF inhibited VEGF induced-proliferation and angiogenesis in HUVECs over a 30-day period.     

Multimodal delivery of irinotecan from microparticles with two distinct compartments

In the last several decades, research in the field of drug delivery has been challenged with the fabrication of carrier systems engineered to deliver therapeutics to the target site with sustained and controlled release kinetics. Herein, we report the fabrication of microparticles composed of two distinct compartments: i) one compartment containing a pH responsive polymer, acetal-modified dextran, and PLGA (polylactide-co-glycolide), and ii) one compartment composed entirely of PLGA. We demonstrate the complete release of dextran from the microparticles during a 10-hour period in an acidic pH environment and the complete degradation of one compartment in less than 24 h. This is in congruence with the stability of the same microparticles in neutral pH over the 24-hour period. Such microparticles can be used as pH responsive carrier systems for drug delivery applications where their cargo will only be released when the optimum pH window is reached. The feasibility of the microparticle system for such an application was confirmed by encapsulating a cancer therapeutic, irinotecan, in the compartment containing the acetal-modified dextran polymer and the pH dependent release over a 5-day period was studied. It was found that upon pH change to an acidic environment, over 50% of the drug was first released at a rapid rate for 10 h, similar to that observed for the dextran release, before continuing at a more controlled rate for 4 days. As such, these microparticles can play an important role in the fabrication of novel drug delivery systems due to the selective, controlled, and pH responsive release of their encapsulated therapeutics.     

Enhancing the anti-ovarian cancer activity of quercetin using a self-assembling micelle and thermosensitive hydrogel drug delivery system

Ovarian cancer, as one of the killers that threaten women’s health, has been studied extensively. As a natural bioflavonoid with prospective effects, quercetin is highly recognized for its anti-cancer applications. However, one of the major challenges that quercetin faces is its poor water solubility, instability in physiological media, and subsequent poor bioavailability. Thus, optimizing the ideal drug delivery options is necessary to facilitate the harnessing of the maximum benefits from quercetin. In this study, a quercetin-loaded thermosensitive injectable hydrogel system (Qu-M–hydrogel composites) was constructed based on nanotechnology. Quercetin was encapsulated into MPEG-PCL (with a high drug loading of 7% and minor particle size of 32 nm) and then added into the blank thermosensitive hydrogel Pluronic F-127. The Qu-M–hydrogel composites showed a much slower release than Qu-M in vivo. Moreover, the cytotoxicity, apoptosis induction, and anti-tumor effects of the Qu-M–hydrogel composites on the abdominal SKOV-3 ovarian cancer mouse models were investigated in vivo. Compared with other groups, the Qu-M–hydrogel composites exhibited improved apoptosis induction and cell growth inhibition effects and in vivo trials showed a better balance between the anti-tumor efficacy in the Qu-M–hydrogel composite group than in other groups at an equal drug dose. In conclusion, the prepared Qu-M–hydrogel composites enhanced the anti-tumor activity by providing a high local quercetin concentration, sustained and stable drug release, extended drug retention inside the tumor, and low toxicity to normal tissues. The Qu-M–hydrogel composites might have great potential for clinical application in anti-ovarian cancer activity.

In this study, a quercetin-loaded thermosensitive injectable hydrogel system (Qu-M–hydrogel composites) was constructed based on nanotechnology.     

Development and in vitro evaluation of a liposomal vaginal delivery system for acyclovir.

Design of a liposome delivery system for vaginal administration of acyclovir, able to provide sustained release and improved bioavailability of the encapsulated drug for the local treatment of genital herpes was investigated. Acyclovir was encapsulated in liposomes prepared by the polyol dilution method, whereby various phospholipid compositions were used: egg phosphatidylcholin (PC)/egg phosphatidylglycerol (PG) 9:1, egg phosphatidylcholine (PC) and egg phosphatidycholine (PC)/stearylamine (SA) 9:3. All liposome preparations were characterized and compared for particle size, polydispersity, encapsulation efficiency and tested for in vitro stability in different media chosen to simulate human vaginal conditions: buffer, pH 4.5 (corresponding to normal human vaginal pH), vaginal fluid simulant (medium developed so as to mimic the fluid produced in the vagina) with or without mucin. To be closer to in vivo application of liposomes and to achieve further improvement of their stability, liposomes were incorporated in a vehicle suitable for vaginal self-administration. Bioadhesive hydrogel made from Carbopol 974P NF resin with adequate pH value and desirable viscosity was chosen as a vehicle for liposomes containing acyclovir. In vitro release studies of liposomes incorporated in the hydrogel proved their applicability as a novel vaginal delivery system with localized and sustained release of encapsulated acyclovir. Even after 24 h of incubation in vaginal fluid simulant more than 35% of the originally encapsulated drug was retained in the hydrogel.     

Efficient tumor regression by a single and low dose treatment with a novel and enhanced formulation of thermosensitive liposomal doxorubicin

We have developed a novel and simplified thermosensitive liposomal formulation (HaT: Hyperthermia-activated cytoToxic) composed of DPPC lipid and Brij78 (96:4, molar ratio). The HaT nanoparticles were loaded with doxorubicin (DOX) with > 95% efficiency when a pH gradient method and a drug/lipid ratio of 1/20 (w/w) were applied. Drug release from the HaT formulation was significantly faster at 40-41 °C (100% release in 2-3 min) with 3.4-fold increased membrane permeability compared to the LTSL (lyso-lipid temperature sensitive liposomes; DPPC: MSPC: DSPE-PEG₂₀₀₀ = 86:10:4, molar ratio), a formulation that is currently in clinical trials. Both formulations displayed similar stability at 37 °C in serum (10-20% release in 30 min), which corresponds to their comparable pharmacokinetics in the unheated mice. An approximately 1.4-fold increased drug delivery to the locally heated tumor (~ 43 °C) was detected with HaT-DOX compared to LTSL-DOX. Moreover, when compared with free DOX, HaT enhanced drug uptake in the heated tumor by 5.2-fold and reduced drug delivery to the heart by 15-fold. A single i.v. treatment with HaT-DOX at 3 mg DOX/kg in combination with localized hyperthermia demonstrated enhanced tumor regression compared to LTSL-DOX and free DOX, and exhibited little toxicity.     

Evaluation of drug delivery profiles in geometric three-layered tablets with various mechanical properties, in vitro–in vivo drug release,and Raman imaging

Even though various multi-layered tablets have been developed for sustained release formulations, evaluations of mechanical properties during dissolution with drug release and imaging in the tablets have been limited. A novel geometric system consisting of an inner immediate release layer and two extended release barrier layers with swellable hydrophilic polymers was suggested as a once-a-day formulation. To evaluate drug release mechanisms with geometric properties, various mechanical characteristics during swelling were investigated to comprehend the relationship among in vitro drug release, human pharmacokinetics, and geometric characteristics. Imaging of drug movement was also studied in real-time using Raman spectroscopy. Drug delivery in the tablets might be divided into three processes through the geometric properties. When exposed to aqueous environments, the drug in the mid-layer was released until wrapped by the swollen barrier layers. Then, the drug in the mid-layer was mainly delivered to the barrier layers and a small amount of the drug was delivered to the contact region of the swollen barrier layers. Finally, the delivered drug to the barrier layers was consistently released out in response to the characteristics of the polymer of the barrier layers. Using Raman spectroscopy, these processes were confirmed in real-time analysis. Moreover, in vitro drug release profiles and human pharmacokinetics showed consistent results suggesting that drug release might be dependent on the various geometric properties and be modified consistently during the formulation development.     

Preparation,pharmacokinetics and pharmacodynamics of ophthalmic thermosensitive in situ hydrogel of betaxolol hydrochloride

Conventional ophthalmic formulations often eliminate rapidly after administration and cannot provide and maintain an adequate concentration of the drug in the precorneal area. To solve those problems, a thermosensitive in situ gelling and mucoadhesive ophthalmic drug delivery system was prepared and evaluated, the system was composed of poloxamer analogs and polycarbophil (PCP) and betaxolol hydrochloride (BH) was selected as model drug. The concentrations of poloxamer 407 (P407) (22% (w/v)) and poloxamer 188 (P188) (3.5% (w/v)) were identified through central composite design-response surface methodology (CCD-RSM). The BH in situ hydrogel (BH-HG) was liquid solution at low temperature and turned to semisolid at eye temperature. BH-HG showed good stability and biocompatibility, which fulfilled the requirements of ocular application. In vitro studies indicated that addition of PCP enhanced the viscosity of BH-HG and the release results of BH from BH-HG demonstrated a sustained release behavior of BH because of the gel dissolution. In vivo pharmacokinetics and pharmacodynamics studies indicated that the BH-HG formulation resulted in an improved bioavailability and a significantly lower intraocular pressure (IOP). The results suggested BH-HG could be potentially used as an in situ gelling system for ophthalmic delivery to enhance the bioavailability and efficacy.     

Synthesis of nanomedicine hydrogel microcapsules by droplet microfluidic process and their pH and temperature dependent release

Chitosan and alginate hydrogels are attractive because they are highly biocompatible and suitable for developing nanomedicine microcapsules. Here we fabricated a polydimethylsiloxane-based droplet microfluidic reactor to synthesize nanomedicine hydrogel microcapsules using Au@CoFeB–Rg3 as a nanomedicine model and a mixture of sodium alginate and PEG-g-chitosan crosslinked by genipin as a hydrogel model. The release kinetics of nanomedicines from the hydrogel were evaluated by simulating the pH and temperature of the digestive tract during drug transport and those of the target pathological cell microenvironment. Their pH and temperature-dependent release kinetics were studied by measuring the mass loss of small pieces of thin films formed by the nanomedicine-encapsulating hydrogels in buffers of pH 1.2, 7.4, and 5.5, which replicate the pH of the stomach, gut and blood, and cancer microenvironment, respectively, at 20 °C and 37 °C, corresponding to the storage temperature of hydrogels before use and normal body temperature. Interestingly, nanomedicine-encapsulating hydrogels can undergo rapid decomposition at pH 5.5 and are relatively stable at pH 7.4 at 37 °C, which are desirable qualities for drug delivery, controlled release, and residue elimination after achieving target effects. These results indicate that the designed nanomedicine hydrogel microcapsule system is suitable for oral administration.

A kind of pH and temperature dependent interpenetrating hydrogel was designed and synthesized via crosslinking of alginate and polyethylene-glycol grafting chitosan by genipin for encapsulated nanomedicine with controlled release.     

Surface-engineered liposomal particles of calcium ascorbate with fenugreek galactomannan enhanced the oral bioavailability of ascorbic acid: a randomized,double-blinded, 3-sequence,crossover study

The antioxidant, anti-inflammatory, immunomodulating, anti-thrombotic, and antiviral effects along with its protective effects against respiratory infections have generated a great interest in vitamin C (vitC) as an attractive functional/nutraceutical ingredient for the management of COVID-19. However, the oral bioavailability and pharmacokinetics of vitC have been shown to be complex and exhibit dose-dependent non-linear kinetics. Though sustained-release forms and liquid liposomal formulations have been developed, only marginal enhancement was observed in bioavailability. Here we report a novel surface-engineered liposomal formulation of calcium ascorbate (CAAS), using fenugreek galactomannan hydrogel in powder form, and its pharmacokinetics following a randomized, double-blinded, single-dose, 3-way crossover study on healthy human volunteers (n = 14). The physicochemical characterization and in vitro release studies revealed the uniform impregnation of CAAS liposomes within the pockets created by the sterically hindered galactomannan network as multilaminar liposomal vesicles with good encapsulation efficiency (>90%) and their stability and sustained-release under gastrointestinal pH conditions. Further human studies demonstrated >7-fold enhancement in the oral bioavailability of ascorbate with a significant improvement in pharmacokinetic properties (C_max, T_max, T_1/2, and AUC), compared to the unformulated counterpart (UF-CAAS) when supplemented at an equivalent dose of 400 mg of CAAS as tablets and capsules.

A green process to modulate the surface properties of liposome was reported using fenugreek galactomannan hydrogel and successfully applied to vitamin C with significant enhancement in human oral bioavailability.     

Nanostructured liquid crystalline particles provide long duration sustained-release effect for a poorly water soluble drug after oral administration

This study is the first to demonstrate the ability of nanostructured liquid crystal particles to sustain the absorption of a poorly water soluble drug after oral administration. Cubic (V₂) liquid crystalline nanostructured particles (cubosomes) formed from phytantriol (PHY) were shown to sustain the absorption of cinnarizine (CZ) beyond 48 h after oral administration to rats. Plasma concentrations were sustained within the range of 21.5 ± 1.5 ng/mL from 12 to 48 h. In stark contrast, cubosomes prepared using glyceryl monooleate (GMO) did not sustain the absorption of CZ and drug concentrations fell below quantifiable levels after 24 h. Sustained absorption of CZ from PHY cubosomes lead to a significant enhancement (p < 0.05) in oral bioavailability (F% = 21%) compared to a CZ suspension (9%) and oleic acid emulsion (12%). Analysis of the nanostructured particles in simulated gastric and intestinal fluids using small angle x-ray scattering (SAXS) revealed that the V₂Pn3m nanostructure of PHY cubosomes was maintained for extended periods of time, in contrast to GMO cubosomes where the V₂Im3m nanostructure was lost within 18 h after exposure, suggesting that degradation of the LC nanostructure may limit sustained drug release. In addition, PHY cubosomes were shown to be extensively retained in the stomach (> 24 h) leading to the conclusion that in the case of non-digestible PHY cubosomes, the stomach may act as a non-sink reservoir that facilitates the slow release of poorly water soluble drugs, highlighting the potential use of non-digestible LC nanostructured particles as novel sustained oral drug delivery systems.     

Controlled delivery of nanosuspensions from osmotic pumps: zero order and non-zero order kinetics

Nanosuspensions have gained great interest in the last decade as a formulation tool for poorly soluble drugs. By decreasing particle sizes nanosuspensions enhance dissolution rate and bioavailability of the active pharmaceutical ingredient. Micro-osmotic pumps are widely used in experimental pharmacology and offer a tool of interest for the sustained release of nanosuspensions via the intraperitoneal or subcutaneous application site. The purpose of the present study was to investigate in-vitro the influence of (1) nanosuspension viscosity, (2) pump orifice position and (3) formulation osmolality on the delivery behavior of formulations in implantable osmotic systems. Therefore fenofibrate nanosuspension, methylene blue and fluorescein sodium solutions were chosen as model formulations. They were released in water or isotonic saline solution and drug/dye concentrations were determined by HPLC/UV. Release of nanosuspension particles in low viscous formulations resulted in a burst whereas increasing the viscosity led to the expected zero order delivery. Pumps with upward-positioned orifices released the nanosuspension in a zero order manner. Within the release of dyes, constant delivery could be ensured up to an osmolality of 486 mO sm/kg; above this value premature release of formulation was observed. The results indicate the requirement of in-vitro experiments prior to in-vivo animal testing for determining the release profiles of osmotic pumps.