Release Of Indomethacin Research Articles

Tailoring pH-sensitive carboxymethyl tamarind kernel gum-based hydrogel for an efficient delivery of hydrophobic drug indomethacin

Polyacrylamide hydrogels have gained attention in the drug delivery field for their pH-dependent nature. Nevertheless, their limited degradability and lower entrapment efficiency for hydrophobic drugs hinder their utility in controlled drug release. This research aims to design a degradable pH-sensitive hydrogel for delivering the hydrophobic drug indomethacin to the colon. This work developed and optimized the hydrogels based on β-cyclodextrin, carboxymethyl tamarind kernel gum, and polyacrylamide with varying amounts of polyethylene glycol diacrylate. The optimized hydrogel exhibits 76.52 % gel fraction, 89.21 % porosity, 1000.27 % swelling, and 90.0 % equilibrium water content. The hydrogel was characterized using Attenuated Total Reflection-Fourier Transform Infrared spectroscopy, confirming the successful crosslinking of the synthesized hydrogel. Powder X-ray Diffraction revealed their amorphous nature while Scanning Electron Microscopy showed a porous surface morphology of the hydrogel. Moreover, rheology confirmed the hydrogel's elastic nature. Notably, the hydrogel demonstrated a drug release of 60.26 % at pH 7.4. Kinetic modelling of indomethacin release data indicated a Fickian diffusion release mechanism. Cytotoxicity tests on HCT-116 cells showed 79 % viability, and the hydrogel fully degraded within 10 days. These results confirmed the potential of synthesized β-CD/PAM/CMTKG hydrogel for controlled indomethacin delivery to the colon.

An advanced ultrasound-activated drug delivery system with piezocatalytic MoS2 nanoflowers for treating patent ductus arteriosus

Patent ductus arteriosus (PDA) is a prevalent cardiovascular anomaly that leads to considerable morbidity and mortality in premature infants. Although pharmacological interventions are commonly used for treatment, they often have notable adverse effects. This study introduces an innovative approach: a controlled drug delivery system that utilizes piezocatalyst nanocarriers produced through hydrothermal techniques. The synthesized nanoparticles undergo thorough characterization to assess their structural and morphological properties. Through ultrasound treatment, precise drug loading and efficient release of indomethacin (IDM) from chitosan (CS) stabilized molybdenum disulfide nanoflowers (MoS2-CS-IDM) are achieved. By harnessing ultrasound-induced reactive oxygen species, this method enables targeted drug delivery. Importantly, the nanoparticles demonstrate an approximately 60 % decrease in PGE2 concentrations, indicating their potential as anti-inflammatory agents. The favorable interaction of the nanoparticles with rat aortic smooth muscle cells and the successful closure of the ductus arteriosus in fetal Wistar rats validate their therapeutic effectiveness in vivo. In conclusion, the piezocatalyst-based drug delivery system presented in this study holds promise for versatile, biocompatible, and controlled drug release, with significant implications for therapeutic applications in PDA and potentially beyond.

Optimizing Formulation Conditions of PLGA Microparticles to Enhance Indomethacin Encapsulation

AbstractDrug delivery systems can avoid the drawbacks of Indomethacin (IND), a non‐steroidal anti‐inflammatory drug used to treat osteoarthritis and arthritis, which requires high doses to reach therapeutic plasma levels leading to significant systemic side effects. This study aims to optimize poly(lactic‐co‐glycolic acid) (PLGA) microparticles (MPs) for intra‐articular IND administration. MPs are prepared by solvent evaporation and freeze‐dried for stability. Initial formulations with Tween 80 yield rubbery samples with low drug loading (1%); replacement of Tween 80 with Gelatin produces a stable powder with syringable MPs (particles size: 7 µm), although, DL (3%) and EE (30%) remain suboptimal, due to IND polymorphic transformation. Differential Scanning Calorimetry and Fourier‐Transform Infrared spectroscopy demonstrate a molecular dispersion of IND in PLGA. Adjusting the aqueous phase to pH 3 in the formulation process, i.e below IND pKa, significantly enhances EE (90%) due to the reduction of drug solubility in the external aqueous phase. In vitro release study shows prolonged IND release over several days, confirming an effective drug encapsulation. This study provides a foundational framework toward the optimization of the successful encapsulation of IND in PLGA MPs, potentially advancing future clinical applications of such drug delivery systems.

Patient-focused programable release indomethacin tablets prepared via conjugation of hot melt extrusion (HME) and fused depositional modeling (FDM) -3D printing technologies

Indomethacin (IND) eases the chronic pain caused by Juvenile idiopathic arthritis (JIA) in clinic, but it was reported that it has dose-related side effects such as gastrointestinal irritations and potential damage to nervous system. So, there is a considerable demand for offering effective, safety, and quality IND dosages for individual pediatric and youth patients. The main aim of this work is to on-demand manufacture personalized and programmable release IND tablets via combining hot melt extrusion (HME) and 3D printing technologies based on the structure-release correlations. IND loaded filaments were extruded and then the tablets were designed and printed. A series of physical and chemical characterization studies were also conducted, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), hot stage polarized light microscopy (PLM), texture analysis, and in vitro drug release studies. The results showed that IND was dispersed in HPMCAS matrix and formed amorphous solid dispersions (ASDs). Additionally, the in vitro drug release studies demonstrated that the release of IND can be programmed via manipulating 3D structure design. The mathematical model to predict the IND from structural designed tablets was obtained and two tablets (T-v1 and T-v2) were printed to validate such model, where the fitting coefficient are 0.9964 and 0.9965, respectively. This study suggested that combining HME and 3D printing technologies could be an optimal approach for personalized and precision drug delivery dosage development.

Ultrasound-guided drug delivery system utilizing piezocatalytic MoS2 nanomaterials for anti-inflammatory therapy

Traditional drug delivery systems lack the potential of controlled drug release, thereby decreasing drug utilization and release efficiency. Herein, a next generation of stimuli-responsive drug delivery platform is designed based on piezocatalytic molybdenum disulfide nanoflowers (MoS2 NFs) which can be triggered by ultrasound (US) stimulation for effective acute inflammation therapy. Under US irradiation, MoS2 NFs undergoes piezocatalysis to generate reactive oxygen species (ROS) owing to piezoelectric polarization, thus releasing loaded anti-inflammatory drug Indomethacin (IND) to the targeted inflammation site. The cumulative release of IND elevated significantly with the increase in the duration for US exposure due to the amplified ROS generation, which displayed a highly controllable nature of the as-designed drug delivery platform. For convenient applications, the IND loaded MoS2 NFs (IND@MoS2 NFs) was functionalized onto commercial dressings and their tunable in-vivo drug release performance was demonstrated in paw edema model. IND@MoS2 NFs upon US irradiation, controllably released IND into the site-specific inflamed paw which significantly inhibited 56 % of paw swelling in 6 h by suppressing the infiltration of neutrophils and expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α). The highly controllable drug delivery system holds great potential in facilitating personalized, user-friendly theranostic applications with improved patient outcomes.

Formulation and Evaluation of Indomethacin Sustained Release Tablet by using Natural Polymers

Arthritis is most prevalent disorder and Indomethacin is choice of drug for arthritis. Oral route is most preferred route of drug administration and tablets are the more convenient dosage form. In present research natural polymers guar gum and xanthan gum were used to make sustained release tablet of Indomethacin. Indomethacin release from the tablets was studied in phosphate buffer pH 7.2. The drug release pattern of six different formulations in which xanthan gum and guar gum were used as a retarding material in different proportions was shown in table no. 6. The formulation F1 releases (75.20%) upto 12 hrs whereas the formulation F2 releases the drug (98.81%) in same time. The formulations F3, F4, F5 and F6 release 98.32%, 99.29%, 98.79% and 82.40% respectively. The dissolution pattern of both gums was similar i.e. with drug to polymer ratio (1:1). In present work F1 shows best sustained release upto 12 hrs in which Drug to Polymer ratio was 1:1:0 (Drug : Xanthan gum : Guar gum). In formulation F2 drug release was not sustained and complete release occurs in 12 hrs where the Drug to Polymer ratio was 1:1.67:0 (Drug: Xanthan gum : Guar gum). It was found that on the concentration of xanthan gum decreases the release rate of the drug also decreases. For sustain release there is not much role of Guar Gum reported. Indomethacin drug has been selected which has half-life 4.5 hrs. Hence the present work, an attempt has been made to provide sustained release drug delivery using polymers with Indomethacin as the model drug. Xanthan gum was best able to retard Indomethacin release mechanism even in the presence of a polymer. Polymer can be used to formulate successful sustained release Indomethacin matrix tablets that have desirable characteristics.

Single-Component Dual-Functional Autoboost Strategy by Dual Photodynamic and Cyclooxygenase-2 Inhibition for Lung Cancer and Spinal Metastasis.

Coloading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy. However, it is difficult to load positively charged photosensitizers and negatively charged adjuvants into the same nanomaterial and further regulate drug release simultaneously. Herein, a single-component dual-functional prodrug strategy is reported for tumor treatment specifically activated by tumor microenvironment (TME)-generated HOCl. A representative prodrug (DHU-CBA2) is constructed using indomethacin grafted with methylene blue (MB). DHU-CBA2 exhibited high sensitivity toward HOCl and achieved simultaneous release of dual drugs in vitro and in vivo. DHU-CBA2 shows effective antitumor activity against lung cancer and spinal metastases via PDT and cyclooxygenase-2 (COX-2) inhibition. Mechanistically, PDT induces immunogenic cell death but stimulates the gene encoding COX-2. Downstream prostaglandins E2 and Indoleamine 2,3 dioxygenase 1 (IDO1) mediate immune escape in the TME, which is rescued by the simultaneous release of indomethacin. DHU-CBA2 promotes infiltration and function of CD8+ T cells, thus inducing a robust antitumor immune response. This work provides an autoboost strategy for a single-component dual-functional prodrug activated by TME-specific HOCl, thereby achieving favorable tumor treatment via the synergistic therapy of PDT and a COX-2 inhibitor.

Electrochemical and Spectroscopic Studies Performed for Indomethacin and 1-Naphthol Incorporated in 1-Butyl-3-methyl-imidazolium Bis(2-ethylhexyl) Sulfosuccinate Vesicles to Investigate Them as a Potentially pH-Sensitive Nanocarrier.

Characterization studies of 1-butyl-3-methyl-imidazolium bis(2-ethylhexyl) sulfosuccinate vesicles at different pH values have been carried out by using liquid surface tension, transmission electron microscopy, and dynamic light scattering. The results show that there are no vesicle changes in its size and negative Z potential at pH 3, 6, and 10. Furthermore, indomethacin and 1-naphthol, both pH-dependent, electroactive, and fluorescence probes, were used to further characterize the bilayer employing electrochemical and emission techniques. The partition of indomethacin and 1-naphthol between the water and bilayer pseudophases only occurs for the neutral species and does not happen for the anionic species because the highly negative Z bilayer potential prevents incorporation due to negative repulsion. For the neutral species, the partition constant values were evaluated by square wave voltammetry and emission spectroscopy. Finally, for the indomethacin incorporated into the vesicle bilayer at pH 3, the release profile was monitored over time at pH 6. It was found that a change in the pH values causes the complete release of indomethacin after 25 min, which led us to think that the vesicles presented in this work can be used as a pH-sensitive nanocarrier for neutral pH-sensitive drugs.

Fluorescent Composite Cotton Fabric Modified with Crosslinked Chitosan for Theranostic Applications

Developing multifunctional textile material for wound dressing is challenging due to the variety of wounds and their differing healing stages. Therefore, theranostics replaces the traditional approach to provide patient comfort and accelerated healing. In this study, we developed and compared three different materials. For this purpose, for the first time, chitosan was modified with 4-nitro-1,8-naphthalic anhydride in N,N-dimethylformamide (DMF) suspension, and subsequent nucleophilic substitution of the nitro group with N,N-dimethylamino group, whereby chitosan with a yellow color and fluorescence was obtained. Cotton fabric was impregnated successively with a citric acid solution and solution from chitosan and chitosan modified with 1,8-naphthalimide fluorophore (CN material). The same experimental protocol was applied for the second material, but indomethacin was added to the chitosan solution (CNI material). The third material was prepared similarly to the second but was immersed in an alginate solution as a last step (CNIA material). The obtained materials have been characterized by optical and scanning electron microscopy and thermal analysis (TG-DTA-DTG). Indomethacin release from composite materials and hydrogel swelling and erosion in phosphate buffer pH 7.4 at 37 °C was examined using gravimetric analysis, UV-vis absorption, and fluorescence spectroscopy. The antimicrobial activity of the cotton samples has been evaluated against B. cereus and P. aeruginosa as model bacterial strains. The analysis showed that CN material inhibited about 98.8% of the growth of P. aeruginosa and about 95.5% of the growth of B. cereus. Other composite materials combine antimicrobial properties with a sustained release of biologically active substances that can observed visually.

Anti-Adhesive Resorbable Indomethacin/Bupivacaine-Eluting Nanofibers for Tendon Rupture Repair: In Vitro and In Vivo Studies.

The treatment and surgical repair of torn Achilles tendons seldom return the wounded tendon to its original elasticity and stiffness. This study explored the in vitro and in vivo simultaneous release of indomethacin and bupivacaine from electrospun polylactide-polyglycolide composite membranes for their capacity to repair torn Achilles tendons. These membranes were fabricated by mixing polylactide-polyglycolide/indomethacin, polylactide-polyglycolide/collagen, and polylactide-polyglycolide/bupivacaine with 1,1,1,3,3,3-hexafluoro-2-propanol into sandwich-structured composites. Subsequently, the in vitro pharmaceutic release rates over 30 days were determined, and the in vivo release behavior and effectiveness of the loaded drugs were assessed using an animal surgical model. High concentrations of indomethacin and bupivacaine were released for over four weeks. The released pharmaceutics resulted in complete recovery of rat tendons, and the nanofibrous composite membranes exhibited exceptional mechanical strength. Additionally, the anti-adhesion capacity of the developed membrane was confirmed. Using the electrospinning technique developed in this study, we plan on manufacturing degradable composite membranes for tendon healing, which can deliver sustained pharmaceutical release and provide a collagenous habitat.

Rapid Indomethacin Release from Porous Pectin Particles as a Colon-Targeted Drug Delivery System.

The conventional pectin delivery systems in the colon are often impaired by a slow release rate. Nanostructured particles, especially porous ones, have gained popularity as drug delivery systems owing to their high mass transfer efficiency. In this research, porous pectin particles were synthesized as drug carriers (using indomethacin as a model drug) via template-assisted spray drying. Specific surface areas of the porous pectin particles have been improved by up to 203 m2 g-1 compared with nonporous particles (1 m2 g-1). The porous structure shortened the diffusion path and improved the release rate of drug molecules. Additionally, the predominant drug release mechanism from porous pectin particles is Fickian diffusion, which is different from the combination of erosion and diffusion mechanism observed for nonporous particles. As a result, these porous drug-loaded pectin particles demonstrated rapid drug release rates of up to three times faster than nonporous particles. Control of the release rate could be achieved by changing the porous structure of the particles. This strategy is an efficient means to synthesize porous particles allowing rapid drug release into the colonic target.

Amorphous solid dispersions in high-swelling, low-substituted hydroxypropyl cellulose for enhancing the delivery of poorly soluble drugs

Amorphous solid dispersions (ASDs) based on water-insoluble hydrophilic polymers can sustain supersaturation in their kinetic solubility profiles (KSPs) compared to soluble carriers. However, in the limit of very high swelling capacity, the achievable extent of drug supersaturation has not been fully examined. This study explores the limiting supersaturation behavior of ASDs of poorly soluble indomethacin (IND) and posaconazole (PCZ) based on a high-swelling excipient, low-substituted hydroxypropyl cellulose (L-HPC). Using IND as a reference, we showed that the rapid initial supersaturation buildup in the KSP of IND ASD can be simulated through sequential IND infusion steps, however at large times the KSP of IND release from ASD appears more sustained than direct IND infusion. This has been attributed to potential trapping of seed crystals generated in the L-HPC gel matrix thus limiting their growth and rate of desupersaturation. Similar result is also expected in PCZ ASD. Furthermore, the current drug loading process for ASD preparation resulted in the agglomeration of L-HPC based ASD particles, producing granules of up to 300–500 µm (cf. 20 µm individual particle), with distinct kinetic solubility profiles. This feature makes L-HPC particularly suitable as ASD carriers for fine tuning of supersaturation to achieve enhanced bioavailability for poorly soluble drugs.

Dopamine-functionalized pectin-based Pickering emulsion as an oral drug delivery system

Pickering emulsions can be utilized to improve the usage efficiency of water-insoluble drugs as oral drug delivery systems. The present study showed a series of dopamine-functionalized pectin-based Pickering emulsions for anti-inflammatory medication. The dopamine functionalization induced significant differences in wettability, zeta potential, particle size, and PDI value compared with the oxidized pectin. The resultant Pickering emulsions consequently had excellent stability and could be stored for 30 days. Moreover, the morphology of the dried Pickering emulsions was all nano-scale spherical particles. Indomethacin (IND) was used as a water-insoluble drug model. The resultant Pickering emulsion-based drug delivery system showed persistent release of IND for more than 12 h, high pH-responsiveness, and biocompatibility. All the results manifested the excellent potential of dopamine-functionalized pectin-based Pickering emulsions in drug delivery applications. The present work also provided a new approach to preparing Pickering emulsions from modified anionic polysaccharides for delivering the water-insoluble drugs.

Prophylaxis of posterior capsule opacification through autophagy activation with indomethacin-eluting intraocular lens.

Posterior capsule opacification (PCO) is the most common long-term postoperative complication of cataract surgery, leading to secondary vision loss. Optimized intraocular lens (IOL) structure and appropriate pharmacological intervention, which provides physical barriers and biological inhibition, respectively, can block the migration, proliferation, and epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) for PCO prophylaxis. Herein, a novel indomethacin-eluting IOL (INDOM-IOL) with an optimized sharper edge and a sustained drug release behavior was developed for PCO prevention. Indomethacin (INDOM), an ophthalmic non-steroidal anti-inflammatory drug (NSAID) used for postoperative ocular inflammation, was demonstrated to not only be able to suppress cell migration and down-regulate the expression of cyclooxygenase-2 (COX-2) and EMT markers, including alpha-smooth muscle actin (α-SMA) and cyclin D1, but also promote the autophagy activation in LECs. Additionally, autophagy was also verified to be a potential therapeutic target for the down-regulation of EMT in LECs. The novel IOL, serving as a drug delivery platform, could carry an adjustable dose of hydrophobic indomethacin with sustained drug release ability for more than 28 days. In the rabbit PCO model, the indomethacin-eluting IOL showed excellent anti-inflammatory and anti-PCO effects. In summary, indomethacin is an effective pharmacological intervention in PCO prophylaxis, and the novel IOL we developed prevented PCO in vivo under its sustained indomethacin release property, which provided a promising approach for PCO prophylaxis in clinical application.

Controlled release of a non-steroidal anti-inflammatory drug from a photocurable polymeric calcium phosphate cement

In this research, a photocurable composite based on tetracalcuim phosphate ceramic and, hydroxyethyl methacrylate-modified poly(acrylic-maleic acid) was developed and studied as a potential drug delivery system for bone defects. Different concentrations (5, 10 and 20 wt. %) of a non-steroidal anti-inflammatory drug, Indomethacin, were loaded on to the composite and its release behavior was investigated in phosphate buffered solution during 504 h. The obtained release data were fitted by both power law (Peppas) and Weibull equations. The composites were also characterized after different soaking periods using X-ray diffractometry (XRD), scanning electron microscopy (SEM) and Fourier transforming infrared spectroscopy. The results of XRD and SEM analyses revealed the formation of nanosized needle/flake-like apatite crystals on the composites surfaces; however, better apatite formation was observed for the composites loaded with higher amounts of Indomethacin. The morphological observations and quantitative estimations revealed that the loaded composites were gradually degraded in the phosphate-buffered saline. Moreover, a controlled release of Indomethacin was found from the composites in which a higher drug concentration led to a more drug level as well as sustained release profile. In drug release modeling, better regression coefficient was obtained from the Weibull equation, compared to the power law, meaning that the Weibull equation suggests a better description of the indomethacin release from the composites during the whole period of the test. In conclusion, the photocurable composite with apatite formation ability can be successfully used for the controlled release of indomethacin as an anti-inflammatory drug in bone defects.

Electrospun nanofibers using β-cyclodextrin grafted chitosan macromolecules loaded with indomethacin as an innovative drug delivery system

Electrospun nanofibers, as an innovative drug delivery system, provide selective, effective, and safe drug release. The present study aimed to fabricate nanofibers based on β-cyclodextrin grafted chitosan (β-CD-g-CS) macromolecules with incorporated drug via the blend electrospinning technique. The grafting of β-CD onto chitosan (CS) was confirmed by FT-IR, 1H NMR, TGA, XRD, and EDX analysis. Indomethacin was encapsulated in the β-CD-g-CS matrix as blend nanofibers using electrospinning in presence of polyvinyl alcohol (PVA). The SEM images revealed nanofibers with diameters at the nanoscale. The unique features of β-CD-g-CS/PVA as drug delivery system were investigated using indomethacin as a model drug molecule. Controlled release of indomethacin from nanofibers was studied in PBS solution by measuring the absorbance by UV–Vis spectrophotometer. The drug release profile exhibited that the rate of drug release can be tailored by polymer type and changing the drug/polymer ratio. The physicomechanical properties of the developed nanofibers were analyzed by tensile strength and water contact angle. The results demonstrated that β-CD-g-CS revealed enhanced wettability as well as favorable physicomechanical properties. In addition, the growth rate of the L929 cells on the CS and β-CD-g-CS nanofibers was not significantly inhibited and even improved cell proliferation. These findings indicated that β-CD-g-CS nanofibers could be appropriate as a smart drug delivery system for sustained release of indomethacin as an anti-inflammatory medicine in the wound healing and tissue engineering approaches in orthopedic applications.

K-Carrageenan/sericin-based multiparticulate systems: A novel gastro-resistant polymer matrix for indomethacin delivery

This study aimed to develop a natural and multiparticulate carrier of k-carrageenan (k-Car) and sericin (Ser) for encapsulation of indomethacin (IND) in order to minimize gastrointestinal effects caused by immediate-release. Increasing the amount of IND in the formulations subtly reduced the entrapment efficiency (EE) and drug loading (DL) due to matrix saturation. Sericin was essential to improve EE and DL when compared to pure k-Car (EE > 90 % and DL > 47 %) with suitable particle sizes (1.3461 ± 0.1891–1.7213 ± 0.1586 mm). The incorporation and integrity of IND in the particles were confirmed by analytical techniques of HPLC, XRD, FTIR, and SEM. Additionally, the k-Car/Ser matrix was pH-responsive with low IND release at pH 1.2 and extended-release at pH 6.8. The Weibull model had an adequate fit to the experimental data with R2aju 0.950.99 and AIC 82.4–24.9, with curves in parabolic profile (b < 1) and indicative of a controlled drug-release mechanism by diffusion. Besides, k-Car/Ser/IND and placebo were not cytotoxic (cell viability > 85 % at 150–600 μM) for the Caco-2 cell line. Therefore, the polymeric matrix is gastro-resistant, stable, and biocompatible to carry indomethacin and deliver it to the intestinal environment.

Highly Porous and Drug-Loaded Amorphous Solid Dispersion Microfiber Scaffolds of Indomethacin Prepared by Melt Electrowriting

Melt electrowriting (MEW) is an additive manufacturing technology enabling the production of highly porous microfiber scaffolds, suggested in particular for use in biomedical applications, including drug delivery. Indomethacin (IND) is a nonselective anti-inflammatory drug, for which sublingual delivery could offer advantages such as rapid absorption by the veins in the mouth floor while overcoming the side effects of peroral delivery such as damage to the gastrointestinal mucosa barrier. This study introduces MEW as a processing method to obtain rapid-dissolving drug-releasing scaffolds, containing IND as a model drug, for sublingual drug delivery applications. For this, an amorphous solid dispersion (ASD) of IND in combination with a poly(2-oxazoline)-based amphiphilic triblock copolymer excipient is introduced, enabling ultra-high drug loading. We prepared highly porous, melt electrowritten drug-loaded scaffolds with different polymer/IND w/w ratios up to 1:2 and assessed their morphology, amorphicity, and IND release rate. The results show completely amorphous dispersion of the polymer and drug after MEW processing resulting in smooth and uniform fibers and rapid dissolution of the drug-loaded scaffold. These first water-soluble melt electrowritten IND-loaded microfiber scaffolds break ground as a model for rapid sublingual delivery of ultra-high drug-loaded ASDs.

Development of an Intrauterine Device Releasing Both Indomethacin and Levonorgestrel During the First Months of Use: Pharmacokinetic Characterization in Healthy Women.

Post-placement menstrual bleeding pattern changes with intrauterine contraceptives (IUCs), including levonorgestrel-releasing intrauterine systems (LNG-IUS), can be a reason for avoidance or early discontinuation. Prostaglandins play an important role in menstrual bleeding and pain. The key drivers of prostaglandin synthesis are cyclooxygenase (COX) enzymes, which are inhibited by non-steroidal anti-inflammatory drugs. In this study, we report the findings from pharmacokinetic (PK) analyses undertaken with an LNG-IUS (LNG-IUS8) modified with an additional reservoir containing indomethacin (IND). The IND/LNG-IUS8 is a proof-of-concept device studied in a phase II proof-of-concept/dose-finding study. IND/LNG-IUS8 contains the same LNG content as the unmodified LNG-IUS8 (13.5 mg) but was prepared with three different IND doses (low, 6.5 mg; middle, 12.5 mg; and high, 15.4 mg), resulting in different daily release rates. Overall, 174 healthy, premenopausal women were randomized to one of the four treatment arms (low-, middle-, high-dose IND/LNG-IUS8 or LNG-IUS 8). Initial and residual IND and LNG content were collected and the amount of IND and LNG released in vivo over the period of use was calculated. A subset of 62 participants underwent dense blood sampling for PK analysis. Concentrations of IND and LNG in plasma were determined by validated liquid chromatography-tandem mass spectrometry methods and plotted over time. Descriptive statistics were calculated for plasma drug concentrations and PK parameters. High-dose IND/LNG-IUS8 initially released much higher levels of IND than expected based on in vitro release data, followed by a steep decline, with the reservoir emptied by 4.5 months. Middle- and low-dose IND/LNG-IUS8 demonstrated steady sustained release of IND over time, emptying after 7.4 and 8.4 months, respectively. Peak plasma concentrations of IND for low- and middle-dose IND/LNG-IUS8 remained below the 20% maximal inhibitory concentration (IC20) values for COX enzymes. The average daily IND release rate in vivo was 49 µg/day for low-dose and 112 µg/day for middle-dose IND/LNG-IUS8. The IND release rate profile and IND plasma concentrations in vitro both decreased steadily over time with low- and middle-dose IND/LNG-IUS8. The LNG release rate profile was comparable for all IND/LNG-IUS8 dose groups and LNG-IUS8. This PK study demonstrates that two different drugs can be released at different rates from an IUS designed with two drug reservoirs. Inclusion of IND does not impact the LNG PK profile. Low- and middle-dose IND/LNG-IUS8 were associated with a systemic IND exposure that should preclude the occurrence of adverse events typically observed after oral IND dosing. ClinicalTrials.gov identifier number: NCT03562624.

Development and characterization of different dosage forms of nifedipine/indomethacin fixed-dose combinations

Studies have shown that 40 individuals out of 100,000 are diagnosed with rheumatoid arthritis (RA) yearly, with a total of 1.3 million in the United States. Furthermore, the impact of RA in some cases can extend to cardiovascular diseases (CVD), as the studies showed that 84% of RA patients are at risk of developing hypertension. This study aims to design and develop different dosage forms (capsule-in-capsule and three-dimensional (3D) printed tablet) of nifedipine/indomethacin fixed-dose combination (FDC). The hot-melt extrusion (HME) was utilized alone and with fused deposition modeling (FDM) techniques The developed dosage forms were intended to provide delayed-extended and immediate release profiles for indomethacin and nifedipine, respectively. FDC dosage forms were successfully developed and characterized. Nifedipine formulations showed significant improvement in release profiles, having 94% of the drug release at 30 min compared with pure nifedipine, which had a percent release of 2%. Furthermore, the release of indomethacin was successfully delayed at a pH of 1.2 and extended at a pH of 6.8. Differential scanning calorimetry results showed endothermic crystalline peaks at 165 °C and 176 °C for indomethacin and nifedipine, respectively. Moreover, the thermal analysis of all formulations showed the absence of the endothermic peaks indicating complete solubilization of indomethacin and nifedipine in the polymeric carriers. All formulations had post-processing drug content in the range of 95%–98%. Moreover, results from the stability study showed that all formulations were able to remain chemically and physically stable with no signs of recrystallization or degradation. The designed FDC dosage forms could improve the quality of life by enhancing patient compliance and preventing the need for polypharmacy.