Control Of Drug Release Rate Research Articles

Phase-separated polymer blends for controlled drug delivery by tuning morphology

Controlling drug release rate and providing physical and chemical stability to the active pharmaceutical ingredient are key properties of oral solid dosage forms. Here, we demonstrate a formulation strategy using phase-separated polymer blends where the morphology provides a route for tuning the drug release profile. By utilising phase separation of a hydrophobic and a hydrophilic polymer, the hydrophilic component will act as a channelling agent, creating a porous network upon dissolution that will dictate the release characteristics. With ptychographic X-ray tomography and scanning transmission X-ray microscopy we reveal how the morphology depends on both polymer fraction and presence of drug, and how the drug is distributed over the polymer domains. Combining X-ray imaging results with dissolution studies reveal how the morphologies are correlated with the drug release and showcase how tuning the morphology of a polymer matrix in oral formulations can be utilised as a method for controlled drug release.

Fluconazole adsorption and release study using KIT-6 for targeted and controlled drug delivery system

ABSTRACT This study presents the development of a mesoporous silica, i.e. KIT-6 synthesised using the hydrothermal technique, followed by the loading of fluconazole as the model drug using the post-impregnation method. The results of drug entrapment studies exposed that 76% of the drug was entrapped in the silica matrix. The drug release rate was investigated in phosphate buffer with pH = 6.8. The fluconazole-loaded KIT-6 prolonged the drug’s release for 12 hours, ensuring Higuchi’s square root kinetics, with diffusion via the matrix as the releasing mechanism, which revealed that the release rate was under control. The MTT assay-based biocompatibility experiments on Vero cells show that the pure and drug-loaded composite systems have minimal cytotoxicity. Hence, drug delivery and adsorption may be facilitated, and repeated administration of drugs is reduced by a controlled drug release rate using the prepared silicious composite.

Hydroxypropyl methylcellulose phthalate films reinforced with nanocrystalline cassava starch and intended its applications for colonic drug delivery

Controlled-release drug delivery systems are crucial for improving therapeutic efficacy and patient compliance. Hydroxypropyl methylcellulose phthalate (HPMCP) films are promising candidates due to their film-forming properties and tunable release profiles. However, their mechanical properties can limit their applicability. This study aimed to assess the effect of addition of nanocrystalline cassava (NCS) starches to HPMCP films on the physicochemical and mechanical properties and the ability of films to control drug release rate. Reinforced HPMCP films with 2, 4 and 6 % w/w of NCS were characterized as a function of the microstructure, X-ray diffraction pattern, mechanical properties, and dissolution property. It was found that increasing starch amount induced an increase in heterogeneity of the film microstructure and crystallinity. The tensile strength of HPMCP films increased with addition of starches, while the elongation at break decreased. The lowest dissolution in pH 6.8 phosphate buffer solution was found for films containing NCS at 2 and 4 % w/w. For the application purposes, HPMCP containing different amounts of NCS was used to coat over diclofenac sodium tablets. The tablets coated with HPMCP containing 4 % w/w NCS showed the lowest drug release of 73.5 % in pH 6.8 phosphate buffer solution at 240 min. According to our results, the addition of NCS at adequate amount allowed to improve the mechanical properties of HPMCP films and to decrease the drug release rate which is important for the site-specific drug delivery process.

Development of Magnetic Pickering Emulsion for Magnetic Drug Delivery Systems

Abstract We have been investigating magnetic drug delivery systems (MDDS), which can selectively deliver drugs to affected areas within the body using a magnetic field. In this study, we developed Magnetic Pickering Emulsions (MPEs) as a novel drug delivery carrier. MPEs can not only induce and accumulate drugs at the targeted site but also control the drug release rate using a magnetic field. In this study, we prepared MPEs using ferromagnetic magnetite nanoparticles and evaluated the control of drug release rate by the magnetic force. MPEs with a particle diameter of several tens of μm gradually released the encapsulated substance for 60 minutes under an applied magnetic field of less than 3 T. On the other hand, for 30 minutes under a magnetic field of more than 4 T, the release rate increased about 2.6 times faster than that under 3 T. These results indicate that MPEs can control the drug release rate by magnetic force.

Cell Membrane-Derived Nanovehicles for Targeted Therapy of Ischemic Stroke: From Construction to Application.

Ischemic stroke (IS) is a prevalent form of stroke and a leading cause of mortality and disability. Recently, cell membrane-derived nanovehicles (CMNVs) derived from erythrocytes, thrombocytes, neutrophils, macrophages, neural stem cells, and cancer cells have shown great promise as drug delivery systems for IS treatment. By precisely controlling drug release rates and targeting specific sites in the brain, CMNVs enable the reduction in drug dosage and minimization of side effects, thus significantly enhancing therapeutic strategies and approaches for IS. While there are some reviews regarding the applications of CMNVs in the treatment of IS, there has been limited attention given to important aspects such as carrier construction, structural design, and functional modification. Therefore, this review aims to address these key issues in CMNVs preparation, structural composition, modification, and other relevant aspects, with a specific focus on targeted therapy for IS. Finally, the challenges and prospects in this field are discussed.

Effects of polymeric surfactants with low HLB values on drug and excipient release from self-emulsifying drug delivery systems

In this study, we evaluated the effects of polymeric surfactants with low hydrophile–lipophile balance values (PSLH) lauryl PEG-8 dimethicone (LP8D) and Pluronic L121 (P121) on drug and excipient release from self-emulsifying drug delivery systems (SEDDS). Valsartan (logKOW 1.5) was used as a model drug, whereas oleic acid (logKOW 7.64) was loaded in SEDDS as a model excipient. Diffusion of valsartan from oil phase to aqueous phase was significantly reduced when adding 5 % LP8D or P121 into the oil phase consisting of isopropyl myristate:Capmul MCM 4:1 m/m. Drug diffusion reached plateau phases after 72 h compared to 3 h in case of the non-PSLH oil phase. Adding 10 % either LP8D or P121 further decreased drug diffusion to aqueous phase. P121 showed a more controlled drug diffusion profile than LP8D at the same loading level. PSLH were loaded in SEDDS preconcentrates at different concentrations in the ranges of 0–15 % LP8D and 0–10 % P121 m/m to yield emulsion with size ∼200 nm and polydispersity index <0.3 upon dilution. The burst release phases from PSLH loaded SEDDS were suppressed and better controlled with higher PSLH loading ratios. The presence of PSLH in the oil phase could increase intermolecular interactions such as hydrogen bonding and London dispersion forces between PSLH and drug or excipient molecules as shown by FTIR difference spectra. Furthermore, PSLH can accumulate at the oil-water interfacial barrier and increase the activation energy level for solute molecules diffusion, i.e. adding 10 % LP8D led to a 3-fold increase in activation energy for oleic acid. Therefore, incorporation of PSLH in SEDDS formulation could be a potential approach to reduce drug diffusion coefficients, enhance drug affinity to oil phase and control drug release rate.

Drug Delivery of Gelatin Nanoparticles as a Biodegradable Polymer for the Treatment of Infectious Diseases: Perspectives and Challenges.

In recent years, there has been a growing interest in the use of gelatin nanoparticles (GNPs) for the treatment of infectious diseases. The inherent properties of these nanoparticles make them attractive options for drug delivery. Their biocompatibility ensures that they can interact with biological systems without causing adverse reactions, while their biodegradability ensures that they can break down harmlessly in the body once their function is performed. Furthermore, their capacity for controlled drug release ensures that therapeutic agents can be delivered over a sustained period, thereby enhancing treatment efficacy. This review examines the current landscape of GNP-based drug delivery, with a specific focus on its potential applications and challenges in the context of infectious diseases. Key challenges include controlling drug release rates, ensuring nanoparticle stability under physiological conditions, scaling up production while maintaining quality, mitigating potential immunogenic reactions, optimizing drug loading efficiency, and tracking the biodistribution and clearance of GNPs in the body. Despite these hurdles, GNPs hold promising potential in the realm of infectious disease treatment. Ongoing research and innovation are essential to overcome these obstacles and completely harness the potential of GNPs in clinical applications.

Thermosensitive and mucoadhesive hydrogels based on modified alginate as drug carriers

New thermosensitive mucoadhesive hydrogels based on a sodium alginate unsaturated derivative have been synthesized by copolymerization with N,N-diethylacrylamide (DEAAm) in the presence of a crosslinking agent. The formation of covalent bonds between the co-monomers has been shown to cause a significant change in the hydrogel supramolecular structure and makes it possible to regulate the lower critical solution temperature (LCST) of the gels. The possibility of using the hydrogels as drug carriers with a temperature- controlled drug release rate has been demonstrated in experiments in vitro

From nanoscale to microscale hierarchical multifunctional nano borate bioactive glass for efficient wound healing

The unique biodegradation and mineralization properties of nanosized CO32−- containing hydroxyapatite (HCA)-coated BBG (nano-HCA@BG) make it a promising material for soft tissue repair. However, its single-function solid powder form makes it difficult to control drug release rates, limiting its potential in vivo application. To address this challenge, we designed a hierarchical multifunctional composite by incorporating gelatin with nano-HCA@BG loaded with AgNPs. The hierarchical composite achieved a high degree of structural fit from nanometer to micrometer scale, as demonstrated by structural characterization results. The composite showed improved encapsulation of nanodrug and controlled degradation, as confirmed by degradation and antimicrobial property results. Wound healing experiments in vivo revealed efficient encapsulation of nano-HCA@BG through specific combination of gelatin and nano-HCA@BG, leading to improved controlled degradation and biological activity of the glass. The study also developed a dynamic flowing drug loading method that integrated material preparation and drug loading, thus improving the efficiency of drug loading of the nano-HCA@BG. Overall, our study demonstrates a new method for the preparation of hierarchical functional biomaterials of bioglass, laying the foundation for nano-HCA@BG to play an important role in tissue repair. Moreover, our findings suggest that better understanding of the structure and biological properties of nano-HCA@BG could expand its application in other biomedical fields such as drug delivery.

High drug-loading and controlled-release hydroxyphenyl-polyacrylate adhesive for transdermal patch.

Long-acting transdermal drug delivery system (TDDS) requires high drug-loading and drug controlled-release. To simultaneously improve drug-polymer miscibility and realize drug controlled-release, this work aimed to develop a new pressure sensitive adhesive modified with hydroxyphenyl (HP-PSA) by introducing doubly ionic H-bond into drug-PSA interaction. Eight model drugs divided into R3N, R2NH and no N type were chosen to understand the characteristics of the HP-PSA and inner mechanism. The results showed that the doubly ionic H-bond between R3N and R2NH type drugs and HP-PSA, differing from the ionic bond and neutral H-bond, was a reversible and relatively strong interaction. It could significantly enhance their drug-loading by 1.5 to 7 times and control drug release rate to its 1/5 to 1/2 without altering its total release properties, outperforming the commercial Duro-Tak® 87-2510 and Duro-Tak® 87-2852 adhesives. According to the pharmacokinetics results, the high drug-loading patches based on HP-PSA achieved a sustainable plasma drug concentration avoiding burst release, and over 2 times area under concentration-time curve (AUC) as well as 6 times mean residence time (MRT) revealed its potential to realize long-acting drug delivery. Additionally, its safety and mechanical features were satisfied. The mechanism study showed that the repulsion of the ionic drugs in HP-PSA increased drug-loading, and the relatively strong interaction could also control drug release. The incomplete H-bond transfer determined its reversibility, thus making the drug release percentage up to that of non-functional PSA. In conclusion, the high drug-loading efficiency and drug controlled-release capacity of HP-PSA, as well as its unique interaction, would contribute to the development of TDDS. Moreover, the construction of the doubly ionic H-bond would provide further inspiration for various drug delivery systems in the non-polar environment.

On-demand preparation of calcium alginate microspheres via piezoelectric microfluidics

Calcium alginate microspheres (CAMs) have attracted extensive attention as a novel drug carrier due to their cheapness, biodegradability, biocompatibility and nontoxicity. The existing preparation technologies of CAMs require complex process steps and involve multiple types of equipment, which are difficult to achieve the real-time and on-demand supply of microspheres in micro-reaction experiments. In this work, CAMs for prolonged drug release are prepared by the designed piezoelectric microfluidic devices using sodium alginate (NaAlg) and calcium chloride (CaCl 2 ). Specifically, the on-demand CAMs are synthesized timely by piezoelectric micro-jet followed by the transportation of piezoelectric micro-pump. Furthermore, various solution concentrations, main parameters of excitation signal and different nozzle diameters are evaluated in terms of size, morphology and drug release rate. The control method of CAMs’ size is obtained based on the multi-physics coupling analysis. Experimental results show that the doxorubicin hydrochloride loaded CAMs (DOX-CAMs) which can be prepared on demand, have excellent uniformity and dispersion, and the minimum average particle size is about 81.9 µm. The controlled drug release rate of DOX-CAMs reaches 83.2 % after 24 h. Moreover, the piezoelectric microfluidic devices and corresponding control methods may have potentials to be adapted for synthesizing other inorganic composite microspheres. • Piezoelectric microfluidics realize the timely supply of microspheres on demand. • The control strategy of microspheres was obtained by simulation analysis. • Preparation of high-quality microspheres with uniformity and dispersion. • Microspheres have excellent drug release performance.

Plasma polymer barrier layers to control the release kinetics from dissolvable microneedle patches

AbstractDissolving microneedles are a noninvasive transdermal drug delivery platform that offers painless needle‐free patient treatment. Current strategies to control the kinetics of drug release from the polymeric microneedle patches consist of adjusting the bulk polymer formulations and/or encapsulating the cargo in controlled delivery vehicles. Instead, in this study, the drug release rates were altered by modifying the surface properties of the microneedles using plasma polymer coatings with tailored properties. The main advantage of this one‐step, solvent‐free, and scalable method is that it can be applied to any type of microneedles regardless of their drug cargo or bulk material. Octadiene plasma polymer films were found to suppress the burst release effect of otherwise rapidly dissolving microneedles and to reduce the dissolution rate by a factor of four compared to uncoated control patches. The approach presented in this study offers an alternative, highly tunable, and customizable strategy for controlling drug release rate from microneedle patches.

Role of Polymer Concentration and Crosslinking Density on Release Rates of Small Molecule Drugs.

Over the past few years, researchers have demonstrated the use of hydrogels to design drug delivery platforms that offer a variety of benefits, including but not limited to longer circulation times, reduced drug degradation, and improved targeting. Furthermore, a variety of strategies have been explored to develop stimulus-responsive hydrogels to design smart drug delivery platforms that can release drugs to specific target areas and at predetermined rates. However, only a few studies have focused on exploring how innate hydrogel properties can be optimized and modulated to tailor drug dosage and release rates. Here, we investigated the individual and combined roles of polymer concentration and crosslinking density (controlled using both chemical and nanoparticle-mediated physical crosslinking) on drug delivery rates. These experiments indicated a strong correlation between the aforementioned hydrogel properties and drug release rates. Importantly, they also revealed the existence of a saturation point in the ability to control drug release rates through a combination of chemical and physical crosslinkers. Collectively, our analyses describe how different hydrogel properties affect drug release rates and lay the foundation to develop drug delivery platforms that can be programmed to release a variety of bioactive payloads at defined rates.

Effect of neutralization degree of methacrylic acid on hydrogel swelling and drug release

Drug delivery system is an amazing tool which is widely used for drug protection and its controlled release in order to enhance drug bioavailability, reduce side effects and therefore to improve overall therapy. Hydrogels have been attracted great attention as drug carriers due to their great physicochemical properties, similarity to the living tissues and biocompatibility. One group of pH sensitive hydrogels are based on poly(methacrylic acid) (PMAA). These non-toxic hydrogels are used as drug delivery system because they swell as a response to the change in pH of external environment and drug is being released during the process. In present study, in order to improve the control of drug release rate, caffeine was encapsulated in liposomes which were further embedded into PMC hydrogel (PMCL). It was investigated how the change in neutralization degree of methacrylic acid affect the swelling degree of PMCL hydrogels and caffeine release in two environments at 37 °C for 24 h: 0.1 M hydrochloride acid (pH 1) and phosphate buffer with pH value of 6.8 (pH 6.8), as a simulation of pH environment in human stomach and intestines, respectively. Obtained results show that PMCL hydrogels have great potential for controlled release of poorly water-soluble drugs in human intestines.

Extraction kinetic model of polysaccharide from Codonopsis pilosula and the application of polysaccharide in wound healing

The crude polysaccharide (CPNP) of Codonopsis pilosula was obtained by hot-water extraction technology. The extraction kinetic model established according to Fick’s first law of diffusion and related parameters of polysaccharide was studied. CPNP microcapsules were prepared by blending with sodium alginate, Ca2+ ions and crude CPNP. The quality control (drug loading rate, embedding rate and release rate, etc) of CPNP microcapsules were analyzed by pharmacopeas standards. The structure feature of CPNP microcapsules also were determined with various methods. The wound healing ability of CPNP microcapsules loading with different concentration of CPNP was evaluated using the rat wound model. The activity of various enzymes and the expression levels of pro-inflammatory factors in the model skin tissue also were determined by enzyme linked immunosorbent assay (ELISA). Hematoxylin-eosin staining (HE), Masson, immunohistochemistry were used to investigate the external application effect of CPNP microcapsules on skin wound repair. The extraction kinetics of CPNP was established with the linear correlation coefficient (R2) of 0.83–0.93, implied that the extraction process was fitted well with the Fick’s first law of diffusion. The CPNP has good compatibility with sodium alginate and Ca2+ ions by SEM and TEM observation, and the particle size of CPNP microcapsules was 21.25 ± 2.84 μm with the good degradation rate, loading rate (61.59%) and encapsulation rate (55.99%), maximum swelling rate (397.380 ± 25.321%). Compared with control group, the redness, and swelling, bleeding, infection, and exudate of the damaged skin decreased significantly after CPNP microcapsules treatment, and the CPNP microcapsules groups exhibited good wound healing function with less inflammatory cell infiltration. The pathological structure showed that in the CPNP microcapsules group, more newborn capillaries, complete skin structure, and relatively tight and orderly arrangement of collagen fibers were observed in the skin of rats. CPNP microcapsules could effectively inhibit the high expression of pro-inflammatory factors in damaged skin, and significantly increase the contents of related enzymes (GSH-Px, T-AOC, LPO) and collagen fibers. The relative expression levels of genes (VEGF and miRNA21) in the CPNP microcapsules group were higher than those in the model group and the negative group. The above results suggested that the CPNP microcapsules could controlled-release the CPNP to the wound surface, and then played a better role in antibacterial, anti-inflammatory and skin wound repair.

Carboxylated gums as additives in the production of interpenetrating hydrogel beads and slow release of glimepiride

AbstractThe properties of polysaccharide‐based hydrogels can be effectively modified by developing an interpenetrating polymer network (IPN) for the purpose of controlled drug delivery. This study aims to unearth the potential of a more viscous, highly carboxylated xanthan (CX) gum as an additive in the design of IPN hydrogel beads with carboxylated guar (CG) gum and control of glimepiride release in simulated gastrointestinal milieu. The carboxylated gums were characterized by infrared spectroscopy, degree of substitution, and viscosity. The incorporation of CX up to 75% into CG matrix did not alter the spherical morphology of the beads after drug loading and ensured ~69% drug entrapment efficiency. The CX as additive provided compatible environment for drug entrapment. Thermal and x‐ray analyses suggested amorphous dispersion of drug in the IPNs. Depending on the concentration of CX, IPN hydrogels demonstrated variable swelling and drug release rate in simulated gastrointestinal pH. It was noticed that at least 25% CX as an additive could be beneficial in controlling drug release rate from the IPNs. The weight percent of CX influenced the drug release mechanism. Hence, the inclusion of CX as an additive in CG matrix seemed to be a promising approach for controlled drug release and further evaluations in vivo.

Introducing a flexible drug delivery system based on poly(glycerol sebacate)-urethane and its nanocomposite: potential application in the prevention and treatment of oral diseases

In this study, a novel biopolymer based on poly(glycerol sebacic)-urethane (PGS-U) and its nanocomposites containing Cloisite@30B were synthesized by facile approach in which the crosslinking was created by aliphatic hexamethylene diisocyanate (HDI) at room temperature and 80 °C. Moreover, metronidazole and tetracycline drugs were selected as target drugs and loaded into PGSU based nanocomposites. A uniform and continuous microstructure with smooth surface is observed in the case of pristine PGS-U sample. The continuity of microstructure is observed in the case of all bionanocomposites. XRD result confirmed an intercalated morphology for PGSU containing 5 wt% of clay nanoparticles with a d-spacing 3.4 nm. The increment of nanoclay content up to 5%, the ultimate tensile stress and elastic modulus were obtained nearly 0.32 and 0.83 MPa, which the latter was more than eight-fold than that of pristine PGS-U. A sustained release for both dugs was observed by 200 h. The slowest and controlled drug release rate was determined in the case of PGSU containing 5 wt% clay and cured at 80 °C. A non-Fickian diffusion can be concluded in the case of tetracycline release via PGS-U/nanoclay bionanocomposites, while a Fickian process was detected in the case of metronidazole release by PGS-U/nanoclay bionanocomposites. As a result, the designed scaffold showed high flexibility, which makes it an appropriate option for utilization in the treatment of periodontal disease.

Diatom-like silica–protein nanocomposites for sustained drug delivery of ruthenium polypyridyl complexes

Inspired by the unique glass cell wall of diatom, we design a new nanostructure of human serum albumin nanoparticle (HSANP) coated with silica (HSA/SiO2), which consists of a core–satellite assembly of small silica nanoparticles on a single HSANP. The HSA/SiO2 nanoparticles are used for delivering ruthenium polypyridyl complexes into cells. The silica coating increases the Ru loading efficiency, and prevents the burst release of Ru from HSA/SiO2. The Ru release rate can be controlled by adjusting the amount of coated silica on HSANP, affording a drug delivery system with controlled drug release rate. The Ru-HSA/SiO2 nanoparticles show high stability in physiological condition, and significantly increase the Ru uptake into cells, which proceeds via clathrin-mediated endocytosis into the lysosomes. The silica coating takes no effect on the fluorescence intensity and ROS generation of loaded Ru in HSA/SiO2. Furthermore, Ru4-HSA/SiO2 exhibit weak cytotoxicity in dark, however, the nanodrug can be activated by light irradiation and generate ROS to damage cells, thus achieving an excellent photodynamic therapy efficiency. Therefore, the diatom-like nanostructure can function as sustained drug delivery nanocarrier of ruthenium polypyridyl complex and can be used for bioimaging and photodynamic therapy.

Dual Gate-Controlled Therapeutics for Overcoming Bacterium-Induced Drug Resistance and Potentiating Cancer Immunotherapy.

The presence of bacteria in the tumor can cause cancer resistance to chemotherapeutics. To fight against bacterium-induced drug resistance, herein we design self-traceable nanoreservoirs that are simultaneously loaded with gemcitabine (an anticancer drug) and ciprofloxacin (an antibiotic) and are decorated with hyaluronic acid for active tumor targeting. The nanoreservoirs have a pH-sensitive gate and an enzyme-responsive gate that can be opened in the acidic and hyaluronidase-abundant tumor microenvironment to control drug release rates. Moreover, the nanoreservoirs can specifically target the tumor regions without eliciting evident toxicity to normal tissues, kill the intratumoral bacteria, and inhibit the tumor growth even in the presence of the bacteria. Unexpectedly, the nanoreservoirs can activate T cell-mediated immune responses through promoting antigen-presenting dendritic cell maturation and depleting immunosuppressive myeloid-derived suppressor cells in bacterium-infected tumors.

Dual Gate‐Controlled Therapeutics for Overcoming Bacterium‐Induced Drug Resistance and Potentiating Cancer Immunotherapy

AbstractThe presence of bacteria in the tumor can cause cancer resistance to chemotherapeutics. To fight against bacterium‐induced drug resistance, herein we design self‐traceable nanoreservoirs that are simultaneously loaded with gemcitabine (an anticancer drug) and ciprofloxacin (an antibiotic) and are decorated with hyaluronic acid for active tumor targeting. The nanoreservoirs have a pH‐sensitive gate and an enzyme‐responsive gate that can be opened in the acidic and hyaluronidase‐abundant tumor microenvironment to control drug release rates. Moreover, the nanoreservoirs can specifically target the tumor regions without eliciting evident toxicity to normal tissues, kill the intratumoral bacteria, and inhibit the tumor growth even in the presence of the bacteria. Unexpectedly, the nanoreservoirs can activate T cell‐mediated immune responses through promoting antigen‐presenting dendritic cell maturation and depleting immunosuppressive myeloid‐derived suppressor cells in bacterium‐infected tumors.