Carriers For Sustained Drug Delivery Research Articles

Synthesis and characterization of Gellan gum-based hydrogels for the delivery of anticancer drug etoposide

Present research work reports the synthesis of Gellan gum (Gg) and methacrylic acid (MA) based grafted hydrogels (Gg-cl-poly(MA)) crosslinked using N, N′– methylene-bis-acrylamide (MBA) and the evaluation of their efficiency to be used as a sustained drug delivery carrier for anticancer drug i.e., etoposide. Various characterization techniques like Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and scanning electron microscopy (SEM) confirmed the grafting of Gg with MA and the formation of crosslinked Gg-cl-poly(MA) hydrogel polymer. The synthesized hydrogel showed pH-dependent swelling properties and exhibited a maximum swelling capacity of 867 % under optimized environmental conditions. The Gg-cl-poly(MA) was biocompatible and non-cytotoxic, which was confirmed by the hemolytic and cytotoxic tests. The release dynamics of etoposide from the Gg-cl-poly(MA) polymer matrix was checked under specific physiological conditions. Drug release was found to be significantly higher in the acidic medium, followed by the neutral and alkaline medium. This clearly indicated that etoposide drug release through synthesized hydrogel was stomach-specific and it is effective for the treatment of stomach cancer. The release mechanism of the etoposide drug was a Fickian-type diffusion mechanism in the acidic medium and a non-Fickian-type diffusion mechanism in the neutral and alkaline medium. The release profile of the etoposide was best fitted to the first-order rate model. The results showed that the synthesized hydrogel (i.e., Gg-cl-poly(MA)) was biocompatible, non-toxic, and could be used for the treatment of stomach cancer.

Surface Modification of Erythrocytes with Lipid Anchors: Structure-Activity Relationship for Optimal Membrane Incorporation, in vivo Retention, and Immunocompatibility.

Red blood cells (RBCs) are natural carriers for sustained drug delivery, imaging, and in vivo sensing. One of the popular approaches to functionalize RBCs is through lipophilic anchors, but the structural requirements for anchor stability and in vivo longevity remain to be investigated. Using fluorescent lipids with the same cyanine 3 (Cy3) headgroup but different lipid chain and linker, the labeling efficiency of RBCs and in vivo stability are investigated. Short-chain derivatives exhibited better insertion efficiency, and mouse RBCs are better labeled than human RBCs. Short-chain derivatives demonstrate low retention in vivo. Derivatives with ester bonds are especially unstable, due to removal and degradation. On the other hand, long-chain, covalently linked derivatives show remarkably long retention and stability (over 80 days half life in the membrane). The clearance organs are liver and spleen with evidence of lipid transfer to the liver sinusoidal endothelium. Notably, RBCs modified with PEGylated lipid show decreased macrophage uptake. Some of the derivatives promote binding of antibodies in human plasma and mouse sera and modest increase in complement deposition and hemolysis, but these do not correlate with in vivo stability of RBCs. Ultra-stable anchors can enable functionalization of RBCs for drug delivery, imaging, and sensing.

Brij Niosomes as Carriers for Sustained Drug Delivery─A Fluorescence-Based Approach to Probe the Niosomal Microenvironment.

Niosomes were prepared using a triad of polyoxyethylene alkyl ether surfactants. The focus was to elucidate the effects of varying alkyl chain length and varying hydrophilic headgroups on the structure of the niosomes, with an aim to design niosomes for efficient encapsulation and release of both hydrophobic and hydrophilic drugs. The phase transitions of the surfactants were ascertained by differential scanning calorimetry. It was found that the headgroup has a profound influence on the niosomal bilayer. Fluorescent probes Coumarin 153 (C-153) and 1,6-diphenyl-1,3,5-hexatriene were used to probe the structural integrity of the niosomal bilayer under stress conditions. Other aspects of the niosomes were probed by following the aggregation of the dyes fluorescein (FL) and Nile Red, red edge excitation shift, and fluorescence resonance energy transfer (FRET) between them. Fluorescence lifetime imaging microscopy provides proof of the exact location of the donor and acceptor dyes in the niosomes under FRET condition. It was also shown that the niosomes are efficient "carriers" for entrapment and controlled release of the chemotherapeutic drug 5-fluorouracil. It was found that a rigid niosomal bilayer leads to controlled drug release. The present work is relevant for the future use of these niosomes for cargo entrapment.

On the Biocompatibility and Teat Retention of In Situ Gelling Intramammary Formulations: Cattle Mastitis Prevention and Treatment.

Treatment and prevention of cattle mastitis remains a formidable challenge due to the anatomical and physiological constraints of the cow udder. In this study, we investigated polymeric excipients and solvents that can form, (when combined) novel, non-toxic and biocompatible in situ gelling formulations in the mammary gland of bovine cattle. We also report on a new approach to screen intramammary formulations using fresh excised cow teats. Fourteen hydrophilic polymers and six solvents were evaluated for in vitro cytotoxicity and biocompatibility towards cultured bovine mammary epithelial cells (MAC-T), microscopic and macroscopic examination upon contact with excised cow teats. No significant cytotoxicity (p > 0.05) was observed with polyethylene oxides, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium alginate and xanthan gum. Polycarbophil and carbopol polymers showed significantly higher cytotoxicity (p < 0.05). Concentration-dependent cytotoxicity was observed for glycerin, propylene glycol, polyethylene glycol 400, ethanol, N-methyl-2-pyrrolidone and 2-pyrrolidone, with the 2-pyrrolidone solvents showing higher cytotoxic effects (p < 0.05). In situ gelling formulations comprising hydroxypropyl methylcellulose or carboxymethyl cellulose and solvents in specific ratios were biocompatible at higher concentrations with MAC-T cells compared to alginates. All investigated formulations could undergo in situ sol-to-gel phase transformation, forming non-toxic gels with good biocompatibility in excised cow teats hence, showing potential for use as intramammary carriers for sustained drug delivery.

Preparation and evaluation of adipic dihydrazide cross-linked hyaluronic acid microspheres for cephalexin

Hyaluronic acid also called as Hyaluronan, Sodium Hyaluronate (SA), sodium salt form of Hyaluronic acid is a biodegradable, biocompatible, and viscoelastic linear polysaccharide of a wide molecular weight range (1000 to 10,000,000 Da). In this project, described a method for preparing HA microspheres at different pH conditions by adapting a non-toxic and aqueous based crosslinking chemistry for sustained drug delivery of drugs. The derivatization chemistry of HA utilizing adipic dihydrazide has been used to construct hydrogels, applied for microsphere preparation. ADH was coupled efficiently to carbodimide-activated glucoronic acid residues of hyluronans. These ADH modified hyaluronan can be loaded with drug molecules and then cross linked into hydrogel. The drug was present in the bulk of hydrogel droplets which are present in liquid paraffin are precipitated by IPA. Formulating HA microspheres with this method have several advantages. Preliminary studies were conducted to confirm the better ratio of HA and ADH to show maximum entrapment efficiency and drug release. Then microspheres were prepared at different pH conditions and formulations were subjected to evaluation of various parameters like percentage yield, particle size, drug entrapment efficiency, porosity and bulk density, surface morphology, in vitro drug release among which F2B was optimized as best formulation which showed 74.6% entrapment efficiency and above 90% of drug release in 12 hours indicating Hyaluronic acid microspheres can be used as good carriers for sustained drug delivery of drugs.

Chitosan-Based Coacervate Polymers for Propolis Encapsulation: Release and Cytotoxicity Studies

Chitosan-DNA (CS-DNA) and Chitosan-Pectin (CS-P) hydrogels were formulated as a sustained drug delivery carrier for drug delivery. For this, hydrogels were prepared by emulsion technique: mixing aqueous phase of the CS and DNA or P solution with benzyl alcohol using a high-performance dispersing instrument. Green Propolis (GP) was incorporated by imbibition: hydrogels were placed in GP aqueous solution (70 µg/mL) for 2 h. The specimens were freeze-dried and then characterized using different techniques. In vitro cell viability and morphology were also performed using the MG63 cell line. The presence of P was evidenced by the occurrence of a strong band at 1745 cm−1, also occurring in the blend. DNA and CS-DNA showed a strong band at 1650 cm−1, slightly shifted from the chitosan band. The sorption of GP induced a significant modification of the gel surface morphology and some phase separation occurs between chitosan and DNA. Drug release kinetics in water and in saliva follow a two-step mechanism. Significant biocompatibility revealed that these hydrogels were non-toxic and provided acceptable support for cell survival. Thus, the hydrogel complexation of chitosan with DNA and with Pectin provides favorable micro-environment for cell growth and is a viable alternative drug delivery system for Green Propolis.

Chitosan-cellulose hydrogel conjugated with L-histidine and zinc oxide nanoparticles for sustained drug delivery: Kinetics and in-vitro biological studies

Functionalised nanohybrid hydrogel using L-Histidine (HIS) conjugated chitosan, phyto-synthesised zinc oxide nanoparticles (ZNPs) and dialdehyde cellulose (DAC) was formulated as a sustained drug delivery carrier for the polyphenol drugs – Naringenin (NRG), Quercetin (QE) and Curcumin (CUR). A maximum loading efficiency of 90.55 %, 92.84 % and 89.89 %, respectively were optimised for NRG, QE and CUR in the hybrid hydrogel. The maximum drug release was favoured for the optimum drug loading and at pH-5. HIS-chitosan conjugation stabilised the hydrogel and enabled a sustained drug delivery. Drug release kinetics predicted a non-Fickian diffusion-based mechanism along with polymer erosion. Prominent antimicrobial activity against Staphylococcus aureus and Trichophyton rubrum strains were predicted to evolve based on the synergic formulation. Significant biocompatibility towards L929 cells revealed their support for normal cell survival. Anticancer studies towards A431 cells exhibited excellent cytotoxicity with a 15 to 30-fold increase using the hybrid carrier, compared to the free polyphenol drugs.

Fabrication and Characterization of One Interpenetrating Network Hydrogel Based on Sodium Alginate and Polyvinyl Alcohol

One interpenetrating network hydrogel based on sodium alginate (SA) and polyvinyl alcohol (PVA) was synthesized by combining the raw materials of PVA and SA with the double physical crosslinking methods of freezing thawing and Ca2+ crosslinking. The PVA-SA composite hydrogel have been characterized by scanning electron microscopy for surface morphology, infrared spectroscopy for investigating the chemical interactions between PVA and SA, X-ray diffraction for studying the PVA-SA composite structure property and thermal gravimetric for understanding the PVA-SA composite thermal stability. The swelling behavior and the degradation rate of the PVA-SA composite hydrogel were studied in simulated gastrointestinal fluid. Using bovine serum albumin (BSA) and salicylic acid as the model drugs, the release behavior of the PVA-SA composite hydrogel on macromolecular protein drugs and small molecule drug were evaluated. The results showed that the water absorption and degradation ability of the PVA-SA composite hydrogel was much better compared to the pure SA hydrogel or pure PVA hydrogel. The hydrogel exhibited remarkable pH sensitivity and the network was stable in the simulated intestinal fluid for more than 24 h. With the advantages such as mild preparation conditions, simple method, less reagent and none severe reaction, the PVA-SA composite hydrogel is expected to be a new prosperous facile sustained drug delivery carrier.

Co-delivery of metformin and levofloxacin hydrochloride using biodegradable thermosensitive hydrogel for the treatment of corneal neovascularization

Corneal neovascularization (CNV) is one of the major causes of severe disorders in ocular surface. Subconjunctival administration provides a localized and effective delivery of anti-angiogenic agents to inhibit neovascularization. In the present study, the ABA triblock copolymer of poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol)-block-poly(D,L-lactic-co-glycolic acid) (PLGA-PEG-PLGA) was used as a sustained drug delivery carrier for metformin (MET) and levofloxacin hydrochloride (LFH). Both drugs and PLGA-PEG-PLGA copolymers could be easily dissolved in water at low or room temperature and the mixed solution could form a drug-loaded thermosensitive hydrogel in terms of body temperature response. The in vitro release investigation displayed a sustained release of MET and LFH from the formulation for one month. The in vivo efficacy of subconjunctival injection of the MET + LFH loaded thermosensitive hydrogel in inhibiting CNV was evaluated on a mouse model of corneal alkali burn. Compared with the single administration of MET or LFH loaded thermosensitive hydrogel, the MET + LFH loaded thermosensitive hydrogel remarkably inhibited the formation of CNV. The sustained release of MET and an antibiotic (LFH) provides synergistic therapeutic outcome. As a result, the co-delivery of MET and LFH using PLGA-PEG-PLGA thermosensitive hydrogel by subconjunctival injection has great potential for ocular anti-angiogenic therapy.

Preparation of Biodegradable and Elastic Poly(ε-caprolactone-co-lactide) Copolymers and Evaluation as a Localized and Sustained Drug Delivery Carrier.

To develop a biodegradable polymer possessing elasticity and flexibility, we synthesized MPEG-b-(PCL-co-PLA) copolymers (PCxLyA), which display specific rates of flexibility and elasticity. We synthesize the PCxLyA copolymers by ring-opening polymerization of ε-caprolactone and l-lactide. PCxLyA copolymers of various compositions were synthesized with 500,000 molecular weight. The PCxLyA copolymers mechanical properties were dependent on the mole ratio of the ε-caprolactone and l-lactide components. Cyclic tensile tests were carried out to investigate the resistance to creep of PCxLyA specimens after up to 20 deformation cycles to 50% elongation. After in vivo implantation, the PCxLyA implants exhibited biocompatibility, and gradually biodegraded over an eight-week experimental period. Immunohistochemical characterization showed that the PCxLyA implants provoked in vivo inflammation, which gradually decreased over time. The copolymer was used as a drug carrier for locally implantable drugs, the hydrophobic drug dexamethasone (Dex), and the water-soluble drug dexamethasone 21-phosphate disodium salt (Dex(p)). We monitored drug-loaded PCxLyA films for in vitro and in vivo drug release over 40 days and observed real-time sustained release of near-infrared (NIR) fluorescence over an extended period from hydrophobic IR-780- and hydrophilic IR-783-loaded PCxLyA implanted in live animals. Finally, we confirmed that PCxLyA films are usable as biodegradable, elastic drug carriers.

Hydrogels based on copolymers of 2‐hydroxyethylmethacrylate and 2‐hydroxyethylacrylate as a delivery system for proteins: Interactions with lysozyme

ABSTRACTHydrogels have attracted considerable attention due to numerous applications, in particular as contact lenses and carriers for sustained drug delivery. The aim of the present work is to characterize the interactions of copolymer hydrogels consisted of 2‐hydroxyethylmethacrylate (HEMA) and 2‐hydroxyethylacrylate (HEA) with a small protein (lysozyme) and to assess the potential applications of these hydrogels as a drug delivery system for sustained release of protein‐based therapeutics. Physicochemical properties of protein‐loaded hydrogels, as well as lysozyme in vitro loading and release and the conformation of the protein released from hydrogels were studied. The effect of copolymer composition on the protein deposition on hydrogels and protein aggregation in the presence of hydrogels was also assessed. The results show that introduction of HEA into the copolymeric hydrogels enhances their suitability as a delivery system for proteins. Copolymerisation of HEMA and HEA allows controlling the physicochemical properties of hydrogels and the protein release rate. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 44768.

Composite CD-MOF nanocrystals-containing microspheres for sustained drug delivery.

Metal-organic frameworks (MOFs), which are typically embedded in polymer matrices as composites, are emerging as a new class of carriers for sustained drug delivery. Most of the MOFs and the polymers used so far in these composites, however, are not pharmaceutically acceptable. In the investigation reported herein, composites of γ-cyclodextrin (γ-CD)-based MOFs (CD-MOFs) and polyacrylic acid (PAA) were prepared by a solid in oil-in-oil (s/o/o) emulsifying solvent evaporation method. A modified hydrothermal protocol has been established which produces efficiently at 50 °C in 6 h micron (5-10 μm) and nanometer (500-700 nm) diameter CD-MOF particles of uniform size with smooth surfaces and powder X-ray diffraction patterns that are identical with those reported in the literature. Ibuprofen (IBU) and Lansoprazole (LPZ), both insoluble in water and lacking in stability, were entrapped with high drug loading in nanometer-sized CD-MOFs by co-crystallisation (that is more effective than impregnation) without causing MOF crystal degradation during the loading process. On account of the good dispersion of drug-loaded CD-MOF nanocrystals inside polyacrylic acid (PAA) matrices and the homogeneous distribution of the drug molecules within these crystals, the composite microspheres exhibit not only spherical shapes and sustained drug release over a prolonged period of time, but they also demonstrate reduced cell toxicity. The cumulative release rate for IBU (and LPZ) follows the trend: IBU-γ-CD complex microspheres (ca. 80% in 2 h) > IBU microspheres > IBU-CD-MOF/PAA composite microspheres (ca. 50% in 24 h). Importantly, no burst release of IBU (and LPZ) was observed from the CD-MOF/PAA composite microspheres, suggesting an even distribution of the drug as well as strong drug carrier interactions inside the CD-MOF. In summary, these composite microspheres, composed of CD-MOF nanocrystals embedded in a biocompatible polymer (PAA) matrix, constitute an efficient and pharmaceutically acceptable MOF-based carrier for sustained drug release.

Polyelectrolyte complex based on carboxymethyl-kappa-carrageenan and Eudragit RL 30D as prospective carriers for sustained drug delivery

Interpolyelectrolyte complexation between carboxymethyl-kappa-carrageenan (CMKC), and Eudragit RL 30D (ERL) was studied and characterized. The obtained polyelectrolyte complex (PEC) was used to develop bioadhesive matrix tablets aimed to prolong buccal-residence time and sustain drug delivery. The optimum ERL-CMKC complexation weight ratio (7:3) was determined in distilled water using apparent viscosity and turbidity measurements. PEC properties were determined by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction and scanning electron microscopy (SEM). Miconazole matrix tablets were prepared by direct compression. Swelling properties and drug release in phosphate buffer solution medium (PBS, pH 6.8) were reported. Tablets exhibited extremely high swelling properties whereas; the dissolution data were fitted to different dissolution models. The drug release from matrix systems depends on the PEC concentration's and approaches zero order kinetics. Drug release mechanism is controlled by the superposition of diffusion and erosion. The relaxation phenomenon appears to increase along the release process and even overcomes diffusion for some systems. A PEC's optimal proportion of 65.06% in the tablet formula provides a dissolution profile characterized by Korsmeyer–Peppas exponent value (n) exceeding 0.97. The ERL-CMKC polyelectrolyte complex has demonstrated a high potential as an excipient for the production of swellable matrix systems with sustained drug release properties.

Mesoporous silica supraparticles for sustained inner-ear drug delivery.

Mesoporous silica supraparticles (MS-SPs) are prepared via self-assembly of mesoporous silica nanoparticles under capillary force action in confined droplets. The MS-SPs are effective carriers for sustained drug delivery. Animal studies show that these particles are suitable for chronic intracochlear implantation, and neurotrophins released from the MS-SPs can efficiently rescue primary auditory neurons in an in vivo sensorineural hearing loss model.

Synthesis and surface modification of mesoporous silica nanoparticles and its application as carriers for sustained drug delivery

High drug loading is one of the important issues in the drug delivery research, especially the drug delivery system by oral administration. If high drug loading carriers are utilized the times of drug intake could be significantly reduced. Accordingly in this study, ordered mesoporous SBA-15 modified with (3-aminopropyl) triethoxysilane (APTES) was used as a carrier for nonsteroidal anti-inflammatory drug and optimization of the loading process was done. SBA-15 silica material with rope-like morphology was synthesized and modified by post-synthesis method with APTES. The synthesized SBA-15 and modified SBA-15 were characterized by XRD, SEM, thermal analysis and FT-IR spectroscopy. Loading optimization experiments were performed by changing the factors affecting the drug loading, such as temperature, time, stirring rate, Ibuprofen/SBA-15 ratio. The results of drug delivery experiments showed that the surface modification of SBA-15 with amino groups significantly increases the drug loading and decreases the drug delivery rate.

Intra-articular fate of degradable poly(ethyleneglycol)-hydrogel microspheres as carriers for sustained drug delivery

A novel degradable microsphere (MS) for intra-articular drug delivery, composed of a polyethylene glycol (PEG) core containing degradable regions made of short poly-(lactic-co-glycolic acid) (PLGA) sequences - named PEG-hydrogel MS - was injected into the cavity of sheep shoulder joint, and compared to non-degradable MS devoid of hydrolysable crosslinker in terms of location, degradation and inflammation. One week after intra-articular injection both groups of MS were localized beneath the synovial lining of the synovial fringes located at bottom of the shoulder joint, while a fraction of particles remained in synovial fluid. Histological analyses made one and 4 weeks after intra-articular injection showed cell proliferation around the non-degradable MS entrapped within the synovium. By contrast, degradable PEG-hydrogel MS were surrounded by few cells. The degradation of degradable PEG-hydrogel MS within the synovium was slow and was not fully complete after four weeks. Our findings indicate that the tissue entrapment of MS below the synovial lining was independent of the material degradability, while degradable PEG-hydrogel MS are less inflammatory than the non-degradable one. Degradable PEG-hydrogel MS offer several advantages over the non-degradable MS as carriers for a sustained drug delivery in synovial tissue according to the low intensity of inflammatory reaction triggered in synovium.

Doxorubicin conjugated gold nanorods: a sustained drug delivery carrier for improved anticancer therapy.

Theranostic nanoparticles with multifunctional ability have been emerging as a new platform for biomedical applications such as imaging, sensing and drug delivery. Despite gold nanorods (Au NRs) being an excellent nanosource with multifunctional versatility, they have certain limitations in biomedical applications, which include surfactant toxicity, biological stability and controlled drug release kinetics. Herein, we have developed Au NR-doxorubicin conjugates (DOX@PSS-Au NR) with improved drug loading efficiency (55 ± 6%) and minimum CTAB toxicity, by employing Au NRs (4.4 ± 0.5 aspect ratio) coated with poly(sodium 4-styrenesulfonate) (PSS). DOX@PSS-Au NR conjugates exhibited higher biological stability with sustained drug release kinetics at pH 5. The binding events of DOX molecules onto the PSS coated gold nanorods (PSS-Au NRs) were monitored through fluorescence quenching and the longitudinal surface plasmon resonance signals. Furthermore the anti-cancer potential and apoptosis inducing efficiency of DOX@PSS-Au NR conjugates in MCF-7 cells revealed higher therapeutic efficiency than free DOX, as corroborated through morphological assessment and in vitro cytotoxicity assay. In addition, DOX@PSS-Au NR conjugates showed efficient cellular entry and uniform intracellular distribution, suggesting the augmenting effect of chemotherapeutic drugs by Au NRs. Thus DOX@PSS-Au NR conjugates demonstrate significant therapeutic potential, suggesting their potential in anticancer therapy.

Utilization of Hydrophilic Swellable Polymers as Carriers for Sustained Drug Delivery from Matrices and Three Layer Tablet Systems

The purpose of this research was to develop and evaluate different sustained release preparations, using swellable polymers as carriers in the form of matrices and three-layer tablets. These preparations may offer a number of therapeutic advantages over immediate release dosage forms in drug delivery. The materials used for the fabrication of these systems were hydrophilic swellable polymers namely Metolose, Polyox, Xanthan gum and an erodible material Gantrez, acting as drug(diclofenac sodium) carriers. The powder characteristics determined for these polymers suggest good flowability with the exception of Gantrez. The addition of 1% of magnesium stearate resulted in improved flow properties for all polymers including Gantrez. Tablets were prepared by direct compression whereas three-layer tablets were prepared by compressing polymer barrier layers on both sides of the core containing the drug. Our findings show that both preparations exhibit sustained release characteristics; also the structure of the device considerably affects the drug release and the release rate. Furthermore erosion and swelling greatly influence the overall behavior, function and performance of the systems. Finally kinetic analysis studies indicated that the drug release mechanisms were also affected by these effects.