Affect Drug Release Research Articles

Mechanistic Model for Drug Release from PLGA-Based Biodegradable Implants for In Vitro Release Testing: Development and Validation.

Several factors can affect drug release from polylactide coglycolide (PLGA)-based formulations, including polymer and drug properties, formulation components, manufacturing processes, and environmental in vitro or in vivo conditions. To achieve optimal release profiles for specific drug delivery applications, it is crucial to understand the mechanistic processes that determine drug release from PLGA-based formulations. In the current study, we developed a mechanistic model for the in vitro drug release of PLGA-based solid implants. The model accounts for all known critical quality attributes (CQAs) and considers the most important release rate processes, including water or dissolution medium influx into the porous structure of the implant, initial noncatalytic hydrolysis of PLGA, autocatalytic hydrolysis, dissolution of oligomers and monomers into the aqueous medium, the liberation of the trapped solid drug from the polymer matrix, dissolution of the solid drug into the wetted pore network, diffusion of the dissolved drug out of the implant, and distribution of the dissolved drug into the dissolution medium. The model has been validated using in vitro release data obtained from implants of four drugs (buserelin, afamelanotide, brimonidine, and nafarelin). The model presented in this manuscript provides valuable insights into the kinetics and mechanism of drug release from PLGA-based solid implants and has demonstrated the potential for optimizing formulation design. The in vitro release model, coupled with physiologically based pharmacokinetic (PBPK) modeling, can predict the in vivo performance of implants and can be used to support bioequivalence studies in a drug development program.

Exploring pH-Triggered Lamellar to Cubic Phase Transition in 2-Hydroxyoleic Acid/Monoolein Nanodispersions: Insights into Membrane Physicochemical Properties.

Self-assembled lipid nanoparticles (LNPs) are essential nanocarriers for drug delivery. Functionalization of LNPs with ionizable lipids creates pH-responsive nanoparticles that change structures under varying pH conditions, enabling pH-triggered drug release. Typically, bicontinuous cubic phase nanoparticles (Cubosomes) and lamellar structured vesicles (Liposomes) differ in lipid packing statuses, affecting drug release and cellular uptake. However, most research predominantly focuses on elucidating lattice structure changes of these LNPs without a deep investigation of lipid-membrane properties. Addressing this gap, our study delves into the lipid-membrane physicochemical property variations during the lamellar-to-cubic phase transition. Here, we prepared pH-responsive LNPs using 2-hydroxyoleic acid/monoolein (2-OHOA/MO) binary components. Small-angle X-ray scattering (SAXS) revealed a phase transition from lamellar vesicles (Lα) to cubosomes (Im3m/Pn3m) with pH reduction. Laurdan and 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence probes tracked the lipid-water interfacial polarity and lipid-membrane fluidity variations during the phase transition. Raman spectroscopy provided further insights into lipid-membrane lipid chain packing and chain torsion. We observed that the changes in lipid-membrane properties coincided with the lamellar-to-cubic phase transition, emphasizing the interplay between the phase structure and lipid-membrane behaviors in the 2-OHOA/MO system. This study provides insights into the lipid-membrane properties variation during the pH-triggered phase transition in the 2-OHOA/MO system, guiding future research toward more effective and reliable pH-responsive drug delivery platforms.

The influence of milling of ribbons on selected granule quality attributes and carvedilol release from roller-compacted hypromellose-based matrix tablets

Roller compaction is gaining importance in the pharmaceutical industry. This study evaluates the impact of ribbon milling conditions on properties of granules and compression mixtures and on drug release from hypromellose-based matrix tablets prepared with two different fillers. In the first part of the study, design of experiments (DoE) was utilized to investigate the effect of filler type (lactose and microcrystalline cellulose (MCC)), mill type (oscillating, conical and hammer mill), milling speed and the size of screen apertures on selected attributes (granule particle size distribution (PSD), porosity and shape), and on the compressibility and compactibility of compression mixtures. The effect of DoE factors and selected attributes on the release of carvedilol at different timepoints of the release profile (t = 1–7 h) was further assessed. The study showed that drug release was affected by filler type, mill type, and various attributes; however, their effect proved to be complex and strongly related to granule PSD. Therefore, this effect was minimized in the second part of the study, in which tablets containing the same amount of different particle size fractions of granules were prepared with different mills and fillers. The drug release profiles confirmed that drug release is mainly related to differences in filler type and granule PSD. However, they indicate that with lactose mill type also affected drug release, possibly due to differences identified in particle shape.

Impact of manufacturing variables on product performance of contraceptive levonorgestrel intrauterine systems

The development of Levonorgestrel Intrauterine Systems (LNG-IUSs) stands as a formidable challenge due to their intricate design and reliance on specialized manufacturing methods. Pharmaceutical manufacturers face a labyrinth of process variables that demand precise identification and comprehension to establish a robust product design to ensure consistent performance. The current manuscript navigates through this complexity, describing a small-scale processing method for LNG-IUSs via addition and condensation curing processes, as well as investigating the influence of key manufacturing variables on LNG-IUS product performance. Different mixing speeds and time exhibited distinct impact on drug content uniformity within the IUS drug-polymer reservoirs. Surprisingly, no variation in drug release rates were observed. Curing temperature and time were the critical processing parameters of IUSs which were dependent on the polymer type (polydimethylsiloxane, PDMS) and drug loading. At lower curing temperatures, crosslinking in PDMS remained relatively unaffected, irrespective of drug loading. By contrast, elevating curing temperatures resulted in a drastic reduction in PDMS crosslinking densities at higher drug loading. This was attributed to increased drug volume fraction within the matrix, impeding optimal prepolymer chain mobility and rearrangement which is crucial for complete crosslinking. Interestingly, rapid curing led to increased PDMS crystallinity, thereby retarding drug release rates while concurrently compromising mechanical properties. PDMS curing chemistry, such as condensation cure (no filler) and addition cure (cured at room temperature), did not affect drug release rates of the LNG-IUSs. In the condensation cure-based LNG-IUS, the formulations prepared without filler had higher drug release rates than those containing silica or diatomaceous earth fillers. Overall, the present study unravels the intricate interplay between PDMS characteristics, processing variables, and product performance, offering fundamental insights into product design and manufacturing of brand and generic LNG-IUS products.

Effect of hydroxyethyl starch on drug stability and release of semaglutide in PLGA microspheres

The degradation of peptide drugs limits the application of peptide drug microspheres. Structural changes of peptides at the water–oil interface and the destruction of their spatial structure in the complex microenvironment during polymer degradation can affect drug release and in vivo biological activity. This study demonstrates that adding hydroxyethyl starch (HES) to the internal aqueous phase (W1) significantly enhances the stability of semaglutide and optimizes its release behavior in PLGA microspheres. The results showed that this improvement was due to a spontaneous exothermic reaction (ΔH = −132.20 kJ mol−1) facilitated by hydrogen bonds. Incorporating HES into the internal aqueous phase using the water-in-oil-in-water (W1/O/W2) emulsion method yielded PLGA microspheres with a high encapsulation rate of 94.38 %. Moreover, microspheres with HES demonstrated well-controlled drug release over 44 days, unlike the slower and incomplete release in microspheres without HES. The optimized h-MG2 formulation achieved a more complete drug release (83.23 %) and prevented 30.65 % of drug loss compared to the HES-free microspheres within the same period. Additionally, the optimized semaglutide microspheres provided nearly three weeks of glycemic control with adequate safety. In conclusion, adding HES to the internal aqueous phase improved the in-situ drug stability and release behavior of semaglutide-loaded PLGA microspheres, effectively increasing the peptide drug payload in PLGA microspheres.

Preparation of tofacitinib sustained-release tablets using hot melt extrusion technology

This study aimed to develop a tablet that shows a drug release profile similar to the tofacitinib sustained-release tablet (Xeljanz XR®; OROS™) using hot melt extrusion technology. Tofacitinib citrate was selected as the drug. HPMCAS, HPMCP, and Kollidon VA64 were used as thermoplastic polymers to prepare a hot-melt extrudate. The extrudate was obtained from a twin screw extruder and pelletizer. The granules were compressed using a single punch press machine and then coated. TGA, DSC, XRD, FT-IR, and SEM were performed on the hot melt extrudate to understand its physicochemical properties. Dissolution tests were performed using the paddle method (USP Apparatus II). The results showed that the crystallinity state of tofacitinib changed to amorphous after the hot melt extrusion process; however, no chemical change was observed. The drug release profile was similar to that of Xeljanz XR®, which has an initial lag time owing to its OROS™ formulation; a coating process was performed to obtain a similar drug release profile. The lag time was controlled by adjusting the thickness of the coating layer. Moreover, the extrudate size and compression force during tableting did not significantly affect drug release. In conclusion, the new tofacitinib sustained-release tablet prepared using hot melt extrusion showed a drug release behavior similar to that of Xeljanz XR®.

Multivariate Analysis and Computational Predictability of Modified Release Formulation of Chirally Pure Metoprolol Succinate

This study employs computational techniques to predict the performance of a modified-release matrix formulation of chirally pure S (-) Metoprolol Succinate, using a Quality by Design (QbD) approach. The research defines the Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQAs) of the S (-) Metoprolol Succinate matrix formulation. To assess risks, an Ishikawa diagram and Failure Mode Effect Analysis (FMEA) following ICH Q8 guidelines were conducted. The formulation screening process utilized Plackett–Burman design, followed by optimization through Box–Behnken design. The modified-release formulation was developed using high shear granulation, incorporating a combination of high and low viscosity Hydroxypropyl Methylcellulose (HPMC) polymers along with other excipients. The impact of polymer composition and stearic acid on the release profile of S (-) Metoprolol Succinate was investigated, revealing their significant influence on the drug delivery system's desired effect. Specifically, the variables X1: HPMC K4M and X2: HPMC K100M were identified as key factors affecting drug release (Y1). Statistical analysis (ANOVA) confirmed the significance of the selected model, with predicted outcomes aligning well with observed results, comparable to the reference product Seleken® XL range. Both drug content and release performance were found to be similar to the innovator formulation. In summary, this investigation underscores the potential of employing a QbD approach with a combination of low and high viscosity HPMC polymers to achieve precise single-dose delivery of S (-) Metoprolol Succinate.

In situ gastric floating gel of atazanavir sulphate for sustained release: formulation, optimization and evaluation.

Aim: Atazanavir sulphate belongs to BCS class II drug, its oral bioavailability is limited due to its rapid first-pass metabolism and P-gp efflux. Materials & methods: The insitu floating gel using the complexed drug was prepared by ion gelation method and optimized the formulation as per 32 full factorial design. Results: Floating lag time of optimized formulation was found to be 18sand percentage drug release of 94.18±0.18 % at the end of 16h. The concentration of gelling polymer affects drug release and a floating lag time and vice versa. Conclusion: Insitu floating gel of atazanavir sulphate was found promising to sustain drug release due to an increased gastric residence time, which leads to enhanced potential therapy.

3D printed PLGA implants: How the filling density affects drug release

Different types of ibuprofen-loaded, poly (D,L lactic-co-glycolic acid) (PLGA)-based implants were prepared by 3D printing (Droplet Deposition Modeling). The theoretical filling density of the mesh-shaped implants was varied from 10 to 100%. Drug release was measured in agarose gels and in well agitated phosphate buffer pH 7.4. The key properties of the implants (and dynamic changes thereof upon exposure to the release media) were monitored using gravimetric measurements, optical microscopy, Differential Scanning Calorimetry, Gel Permeation Chromatography, and Scanning Electron Microscopy. Interestingly, drug release was similar for implants with 10 and 30% filling density, irrespective of the experimental set-up. In contrast, implants with 100% filling density showed slower release kinetics, and the shape of the release curve was altered in agarose gels. These observations could be explained by the existence (or absence) of a continuous aqueous phase between the polymeric filaments and the “orchestrating role” of substantial system swelling for the control of drug release. At lower filling densities, it is sufficient for the drug to be released from a single filament. In contrast, at high filling densities, the ensemble of filaments acts as a much larger (more or less homogeneous) polymeric matrix, and the average diffusion pathway to be overcome by the drug is much longer. Agarose gel (mimicking living tissue) hinders substantial PLGA swelling and delays the onset of the final rapid drug release phase. This improved mechanistic understanding of the control of drug release from PLGA-based 3D printed implants can help to facilitate the optimization of this type of advanced drug delivery systems.

Facile fabrication of combination delivery of kaempferol and sorafenib with PEGylated gold nanoparticles delivery to breast cancer: Investigation of cytotoxicity and apoptosis induction

Current clinical therapies for invasive breast cancer have low therapeutic effectiveness and substantial systemic adverse effects, leading to poor patient compliance. In this investigation, we developed dual anticancer drugs (sorafenib (SFB) and kaempferol (KMF)) encapsulated in PEGylated gold nanomaterial (PEG-AuNPs@SFB/KMF) for a drug delivery system targeting breast cancer to circumvent this problem. Subsequent research examined whether pH affects drug release. The current study results show that sorafenib and kaempferol work better together than each treatment individually in eliciting cytotoxic effects. In vitro cytotoxicity studies confirmed that PEG-AuNPs@SFB/KMF were more effective than sorafenib alone in MCF-7 and MDA-MB-231 cells, with less toxicity in NIH3T3 cells. The cancer cell proliferation was measured by Click-iT EdU assay, which indicates that the NPs effectively induce apoptosis in cancer cells. The different biochemical staining (acridine orange and ethidium bromide (AO-EB and nuclear staining (DAPI)) methods confirmed the morphological investigation of the cells. PEG-AuNPs@SFB/KMF increased apoptosis ratio, confirmed by flow cytometric analysis via Annexin V-FITC/PI staining methods. Therefore, we believe that the built multifunctional nanocarrier based on developed nanoparticle delivery could be an alternative therapeutic strategy for breast cancer therapy.

Sustained release of salicylic acid from ethyl cellulose microspheres fabricated using quasi-emulsion solvent diffusion method

Delivery of drugs using micro-sized particles is an efficient tool. Using ethyl cellulose (EC) as a polymer and the quasi-emulsion solvent diffusion (QESD) method paves the way for the utilization of a cost-effective polymer and an efficient fabrication method. Poly(vinyl alcohol) in water was used as an external phase while EC and Salicylic acid (SA) were dissolved in dichloromethane as an internal phase. SA is known to inhibit prostaglandins and have an anti-inflammatory effect. Furthermore, it inhibits the formation of bacterial biofilm on surfaces. Microparticles of several variations were successfully fabricated using the QESD method in an efficient time frame. These microparticles ranged in size from 5 to 40 μm for these formulations. Characterization results substantiated the selection of materials used for fabrication. Cytotoxicity showed that these fabrications were biocompatible and did not inhibit cell proliferation. In vitro drug release studies showed that the fabricated EC microparticles were able to sustainably release the drugs contained within them over a 96-h time period, with most of the drug being released after 48 h. This release never exceeded 63% of the total drug content. PEG addition in the fabrication process of formulation ECPSA eliminated burst release, resulting in a sustained release pattern over 48 h, reaching saturation by day 5. While entrapment was dependent on the polymer content, increasing drug content did not significantly affect drug release. Behavioral studies evaluated the microspheres, revealing different kinetic models, including Higuchi in ECSA2 and Korsmeyer-Peppas in ECSA3, ECSA5, ECSA6, and ECPSA, with varying diffusion mechanisms. Future fabrications can be made to increase the porousness of the spheres to increase drug release from the microparticles. Also, drug release studies can be conducted over longer periods of time, and with near-infrared light (NIR) to observe the changes in drug release between the fabrications.

Drug Release from Surfactant-Containing Amorphous Solid Dispersions: Mechanism and Role of Surfactant in Release Enhancement.

To understand how surfactants affect drug release from ternary amorphous solid dispersions (ASDs), and to investigate different mechanisms of release enhancement. Ternary ASDs containing ritonavir (RTV), polyvinylpyrrolidone/vinyl acetate (PVPVA) and a surfactant (sodium dodecyl sulfate (SDS), Tween 80, Span 20 or Span 85) were prepared with rotary evaporation. Release profiles of ternary ASDs were measured with surface normalized dissolution. Phase separation morphologies of ASD compacts during hydration/dissolution were examined in real-time with a newly developed confocal fluorescence microscopy method. The water ingress rate of different formulations was measured with dynamic vapor sorption. Microscopy was employed to check for matrix crystallization during release studies. All surfactants improved drug release at 30% DL, while only SDS and Tween 80 improved drug release at higher DLs, although SDS promoted matrix crystallization. The dissolution rate of neat polymer increased when SDS and Tween 80 were present. The water ingress rate also increased in the presence of all surfactants. Surfactant-incorporation affected both the kinetic and thermodynamics factors governing phase separation of RTV-PVPVA-water system, modifying the phase morphology during ASD dissolution. Importantly, SDS increased the miscibility of RTV-PVPVA-water system, whereas other surfactants mainly affected the phase separation kinetics/drug-rich barrier persistence. Incorporation of surfactants enhanced drug release from RTV-PVPVA ASDs compared to the binary system. Increased drug-polymer-water miscibility and disruption of the drug-rich barrier at the gel-solvent interface via plasticization are highlighted as two key mechanisms underlying surfactant impacts based on direct visualization of the phase separation process upon hydration and release.

Abstract 1529: Characterizing antibody internalization for rational selection of ADC linker design

Abstract Antibody-drug conjugates (ADC), which target a highly potent cytotoxin to a specific protein overexpressed on tumor cells, are a promising class of anticancer therapeutics. In addition to the antibody characteristics, intracellular reactivity of the antibody-cytotoxin linker (which affects drug release) is a key determinant of ADC efficacy. While many different linkers have been used in approved ADCs, the intracellular trafficking profile of an antibody will likely impact the effectiveness of different linkers differently. Here, we determined the cellular internalization of two antibodies, anti-perlecan antibody (‘AM6’), and anti-EGFR antibody (cetuximab; ‘Ctx’), in MDA-MB-231-LM2 cells (a lung-metastatic TNBC cell line). Using live-cell confocal microscopy, we investigated the effect of endocytosis inhibitors on intracellular trafficking of AM6 and Ctx. While AM6 was internalized quicker compared to Ctx, the internalization of both antibodies was reduced significantly by 5-(N-Ethyl-N-isopropyl)-amiloride, a macropinocytosis inhibitor and, to a lesser extent, by chlorpromazine, an inhibitor of clathrin-mediated-endocytosis. The results suggest both AM6 and Ctx were internalized by both macropinocytosis and clathrin-mediated endocytosis. We then investigated whether acidic pH in the lysosomes and the reductive environment in the endosomal vesicles would facilitate drug release from ADC. We conjugated thiol-reactive doxorubicin to reduced interchain disulfides of Ctx via either the acid and glutathione (GSH)-labile pyridinyldithio-hydrazide linker or the non-cleavable C6-maleimide linker. Intracellular doxorubicin release for the two ADCs was evaluated by live-cell confocal microscopy. Doxorubicin was successfully conjugated to Ctx, with a DAR of 4.8 and 8.6 for the cleavable and non-cleavable linkers, respectively. Conjugation of doxorubicin to the antibody was confirmed by fluorescent gel imaging after SDS-PAGE and by using hydrophobic interaction chromatography. Confocal microscopic studies showed that the ADC with cleavable linker resulted in greater doxorubicin accumulation in the nucleus compared to the ADC with non-cleavable linker, which was predominantly sequestered in the lysosomes. These results suggest that the cleavable linker results in better drug release compared to the non-cleavable linker for the Ctx-doxorubicin ADC. Studies examining the effect of linker chemistry on drug release from the anti-perlecan ADC and on the anticancer efficacy of the two ADCs are ongoing. Citation Format: Zekun Shao, Jayanth Panyam. Characterizing antibody internalization for rational selection of ADC linker design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1529.

Studying spatial drug distribution in golf ball-shaped microspheres to understand drug release

Poly (lactic-co-glycolic acid) (PLGA) microspheres have been one of the most successful products for slow drug release. While distribution of drugs in microspheres might be a fundamental factor affecting drug release, it has been often overlooked. Indeed, very few studies are available on the distribution of drugs in microspheres with complex morphology like golf ball-shaped microspheres. In this paper, the distribution of rotigotine in golf ball-shaped microspheres (GSRM) was investigated by argon ion milling, combined with scanning electron microscopy and energy dispersive X-ray spectroscopy (AIM-SEM-EDS). Rotigotine in GSRM was clearly observed in two forms, respectively in an aggregated state and as a molecular dispersion. The distribution of palmitic acid in the microspheres (used as an additive to reduce burst release) was also demonstrated: 10% was found on the microspheres' surface while 90% separated from the polymer to form small particles inside the microspheres onto which rotigotine aggregated through hydrogen bonding interactions. In in-vitro release studies we observed that first the phase-separated palmitic acid/rotigotine particles dissolved and released the drug, followed by the release of the molecularly dispersed rotigotines by osmosis. We also found that rotigotine accelerated the degradation and reduced the glass transition temperature of PLGA, which played an important role as well in the release of the drug from GSRM. Finally, two linear Level A in vitro-in vivo correlations were established and validated, indicating that the in vitro release testing could be a meaningful predictor for the in vivo performance of GSRM. Our work demonstrates the importance of studying drug distribution in complex microspheres to understand drug release.

Controlled Release of Felodipine from 3D-Printed Tablets with Constant Surface Area: Influence of Surface Geometry.

In this study, 3D-printed tablets with a constant surface area were designed and fabricated using polylactic acid (PLA) in the outer compartment and polyvinyl alcohol and felodipine (FDP) in the inner compartment. The influences of different surface geometries of the inner compartment, namely, round, hexagon, square, and triangle, on drug release from 3D-printed tablets were also studied. The morphology and porosity of the inner compartment were determined using scanning electron microscopy and synchrotron radiation X-ray tomographic microscopy, respectively. Additionally, drug content and drug release were also evaluated. The results revealed that the round-shaped geometry seemed to have the greatest total surface area of the inner compartment, followed by square-shaped, hexagon-shaped, and triangle-shaped geometries. FDP-loaded 3D-printed tablets with triangle and hexagon surface geometries had the slowest drug release (about 80% within 24 h). In the round-shaped and square-shaped 3D-printed tablets, complete drug release was observed within 12 h. Furthermore, the drug release from triangle-shaped 3D-printed tablets with double the volume of the inner compartment was faster than that of a smaller volume. This was due to the fact that a larger tablet volume increased the surface area contacting the medium, resulting in a faster drug release. The findings indicated that the surface geometry of 3D-printed tablets with a constant surface area affected drug release. This study suggests that 3D printing technology may be used to develop oral solid dosage forms suitable for customized therapeutic treatments.

Investigations into the use of machine learning to predict drug dosage form design to obtain desired release profiles for 3D printed oral medicines

Three-dimensional (3D) printing, digitalization, and artificial intelligence (AI) are gaining increasing interest in modern medicine. All three aspects are combined in personalized medicine where 3D-printed dosage forms are advantageous because of their variable geometry design. The geometry design can be used to determine the surface area to volume (SA/V) ratio, which affects drug release from the dosage forms. This study investigated artificial neural networks (ANN) to predict suitable geometries for the desired dose and release profile. Filaments with 5% API load and polyvinyl alcohol were 3D printed using Fused Deposition Modeling to provide a wide variety of geometries with different dosages and SA/V ratios. These were dissolved in vitro, and the API release profiles were described mathematically. Using these data, ANN architectures were designed with the goal of predicting a suitable dosage form geometry. Poor accuracies of 68.5% in the training and 44.4% in the test settings were achieved with a classification architecture. However, the SA/V ratio could be predicted accurately with a mean squared error loss of only 0.05. This study shows that the prediction of the SA/V ratio using AI works, but not of the exact geometry. For this purpose, a global database could be built with a range of geometries to simplify the prescription process.

Different drug loading methods and antibiotic structure modulate the efficacy of polydopamine nanoparticles as drug nanocarriers.

The inefficient delivery of antimicrobials to their target is a significant factor contributing to antibiotic resistance. As such, smart nanomaterials that respond to external stimuli are extensively explored for precise drug delivery. Here, we investigate how drug loading methods and the structure of antibiotics impact the effectiveness of photothermally active polydopamine nanoparticles (PDNPs) as a laser-responsive drug delivery system. We examine two loading methods: in-synthesis and post-synthesis, and evaluate how laser irradiation affects drug release. Density functional theory calculations are also performed to gain deeper insights into the drug-PDNP interactions. Our findings point to the critical role of antibiotic structure and drug loading method in the laser-responsive capabilities of PDNPs as drug nanocarriers. Our study offers valuable insights for optimizing the design and efficiency of PDNP-based drug delivery systems.

Ethanol-induced dose dumping from sodium alginate matrix tablets: Investigation of the effects of medium viscosity and pH

In this work, the swelling and disintegration of drug-free sodium alginate (SA) compacts and the release of metformin HCl from SA matrix tablets were investigated in acidic media of different ethanol concentrations (0, 10, 20, and 40 % v/v), pH (1.2 and 4.5) and HPMC K4M concentrations (0–1 % w/v). The investigated dissolution media represented the consumption of different alcoholic beverages, the pH of fasted and fed states, and a range of viscosity resembling diluted homogenized FDA meal. The dissolution efficiency and the time to 50 % release (t50%) were selected as release parameters. It was found that both ethanol concentration and medium pH affected drug release from SA matrix tablets and the swelling of SA compacts. Dose dumping occurred at high ethanol concentration (40 %) at both media pH with almost complete drug release within 15–30 min associated with rapid matrix disintegration. HPMC at 0.5–1 % concentrations increased the medium's viscosity, preventing dose dumping at high ethanol concentrations. Erosion and disintegration of SA compacts were decelerated by increasing HPMC concentration in hydroethanolic media in consonance with decreased release rate from matrix tablets. ANOVA tests showed significant effects of pH and concentrations of ethanol and HPMC in the dissolution medium on the release parameters.

Investigating the influence of ultrasound parameters on ibuprofen drug release from hydrogels.

Hydrogels are promising ultrasound-responsive drug delivery systems. In this study, we investigated how different ultrasound parameters affected drug release and structural integrity of self-healing hydrogels composed of alginate or poloxamers. The effects of amplitude and duty cycle at low frequency (24kHz) ultrasound stimulation were first investigated using alginate hydrogels at 2% w/v and 2.5% w/v. Increasing ultrasound amplitude increased drug release from these gels, although high amplitudes caused large variations in release and damaged the gel structure. Increasing duty cycle also increased drug release, although a threshold was observed with the lower pulsed 50% duty cycle achieving similar levels of drug release to a continuous 100% duty cycle. Poloxamer-based hydrogels were also responsive to the optimised parameters at low frequency (24kHz, 20% amplitude, 50% duty cycle for 30s) and showed similar drug release results to a 2.5% w/v alginate hydrogel. Weight loss studies demonstrated that the 2% w/v alginate hydrogel underwent significant erosion following ultrasound application, whereas the 2.5% w/v alginate and the poloxamer gels were unaffected by application of the same parameters (24kHz, 20% amplitude, 50% duty cycle for 30s). The rheological properties of the hydrogels were also unaffected and the FTIR spectra remained unchanged after low frequency ultrasound stimulation (24kHz, 20% amplitude, 50% duty cycle for 30s). Finally, high-frequency ultrasound stimulation (1MHz, 3W.cm-2, 50% duty cycle) was also trialled; the alginate gels were less responsive to this frequency, while no statistically significant impact on drug release was observed from the poloxamer gels. This study demonstrates the importance of ultrasound parameters and polymer selection in designing ultrasound-responsive hydrogels.

Adsorption and Release Properties of Drug Delivery System Naproxen-SBA-15: Effect of Surface Polarity, Sodium/Acid Drug Form and pH.

Mesoporous silica SBA-15 was prepared via sol-gel synthesis and functionalized with different types of organosilanes containing various organic functional groups: (3-aminopropyl)triethoxysilane (SBA-15-NH2), (3-mercaptopropyl)triethoxysilane (SBA-15-SH), triethoxymethylsilane (SBA-15-CH3), triethoxyphenylsilane (SBA-15-Ph), and (3-isocynatopropyl)triethoxysilane (SBA-15-NCO). The prepared materials were investigated as drug delivery systems for naproxen. As model drugs, naproxen acid (HNAP) and its sodium salt (NaNAP) were used. Mentioned medicaments belong to the group of non-steroidal anti-inflammatory drugs (NSAIDs). The prepared materials were characterized by different analytical methods such as transmission electron microscopy (TEM), infrared spectroscopy (IR), nitrogen adsorption/desorption analysis (N2), thermogravimetric analysis (TG), 1H, 13C and 23Na solid-state nuclear magnetic resonance spectroscopy (1H, 13C and 23Na ss-NMR). The abovementioned analytical techniques confirmed the successful grafting of functional groups to the SBA-15 surface and the adsorption of drugs after the impregnation process. The BET area values decreased from 927 m2 g-1 for SBA-15 to 408 m2 g-1 for SBA-15-NCO. After drug encapsulation, a more significant decrease in surface area was observed due to the filling of pores with drug molecules, while the most significant decrease was observed for the SBA-15-NH2 material (115 m2 g-1 for NaNAP and 101 m2 g-1 for HNAP). By combining TG and nitrogen adsorption results, the occurrence of functional groups and the affinity of drugs to the carriers' surface were calculated. The dominant factor was the volume of functional groups and intermolecular interactions. The highest drug affinity values were observed for phenyl and amine-modified materials (SBA-15-Ph = 1.379 μmol m-2 mmol-1 for NaNAP, 1.761 μmol m-2 mmol-1 for HNAP and SBA-15-NH2 = 1.343 μmol m-2 mmol-1 for NaNAP, 1.302 μmol m-2 mmol-1 for HNAP) due to the formation of hydrogen bonds and π-π interactions, respectively. Drug release properties and kinetic studies were performed at t = 37 °C (normal human body temperature) in different media with pH = 2 as simulated human gastric fluid and pH = 7.4, which simulated a physiological environment. Determination of drug release quantity was performed with UV-VIS spectroscopy. The surface polarity, pH and naproxen form influenced the total released amount of drug. In general, naproxen sodium salt has a higher solubility than its acid form, thus significantly affecting drug release from surface-modified SBA-15 materials. Different pH conditions involved surface protonation and formation/disruption of intermolecular interactions, influencing both the release rate and the total released amount of naproxen. Different kinetic models, zero-order, first-order, Higuchi and Hixson-Crowell models, were used to fit the drug release data. According to the obtained experimental results, the drug release rates and mechanisms were determined.