Development of 3D-printed dual-release fixed-dose combination through double-melt extrusion.

This study aimed to develop a 3D-printed fixed-dose combination tablet featuring differential release of two drugs using double-melt extrusion (DME). The hot-melt extrusion (HME) process was divided into two steps to manufacture a single filament containing the two drugs. In Step I, a sustained-release matrix of acetaminophen (AAP) was obtained through HME at 190 °C using Eudragit® S100, a pH-dependent polymer with a high glass transition temperature. In Step II, a filament containing both sustained-release AAP from Step I and solubilized ibuprofen (IBF) was fabricated via HME at 110 °C using a mixture of hydroxy propyl cellulose (HPC-LF) and Eudragit® EPO, whose glass transition temperatures make them suitable for use in a 3D printer. A filament manufactured using DME was used to produce a cylindrical 3D-printed fixed-dose combination tablet with a diameter and height of 9 mm. To evaluate the release characteristics of the manufactured filament and 3D-printed tablet, dissolution tests were conducted for 10 h under simulated gastrointestinal tract conditions using the pH jump method with the United States Pharmacopeia apparatus II paddle method at 37 ± 0.5 °C and 50 rpm. Dissolution tests confirmed that both the sustained-release and solubilized forms of AAP and IBF within the filament and 3D-printed tablet exhibited distinct drug-release behaviors. The physicochemical properties of the filament and 3D-printed tablet were confirmed by thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and Fourier-transform infrared spectroscopy. HME transforms crystalline drugs into amorphous forms, demonstrating their physicochemical stability. Scanning electron microscopy and confocal laser scanning microscopy indicated the presence of sustained AAP granules within the filament, confirming that the drugs were independently separated within the filament and 3D-printed tablets. Finally, sustained-release AAP and solubilized IBF were independently incorporated into the filaments using DME technology. Therefore, a dual-release 3D-printed fixed-dose combination was prepared using the proposed filament.

High Dose Pantoprazole for Gastroesophageal Reflux Disease: Need, Evidence, Guidelines and Our Experience.

Gastroesophageal reflux disease (GERD) has a pooled prevalence of 15.2% in India with varying presentation in different subset of patients. The approach towards the management of GERD includes use of monotherapy or a combination of OTCs like antacids and/or prescription drugs like H2 receptor antagonists and proton pump inhibitors (PPI). Better efficacy and safety profile of PPIs have contributed to its wide spread use as compared with other drugs for the same indication. Among PPIs, most of the healthcare professionals prefer to prescribe pantoprazole in India. Standard dose of Pantoprazole (40 mg) is unable to meet the needs in case of extraesophageal symptoms, partial responders, patients with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), or severe presentation in cases of overweight/obese patients. Multiple guidelines recommend doubling the dose of PPI in such cases. Twice daily dosing of PPI may reduce compliance. Thus, there is a need for a higher dose of Pantoprazole (80 mg) to be prescribed once daily in these cases so that improved compliance leads to better outcomes. The use of dual release Pantoprazole 80 mg may help to improve compliance and also enhance the time for which acid suppression takes place. In this review, we discuss the use of higher dose PPI based on scientific evidence and experience of clinicians for the same. How to cite this article: Upadhyay R, Soni NK, Kotamkar AA, et al. High Dose Pantoprazole for Gastroesophageal Reflux Disease: Need, Evidence, Guidelines and Our Experience. Euroasian J Hepato-Gastroenterol 2024;14(1):86-91.

Development of a biodegradable polymer-based implant to release dual drugs for post-operative management of cataract surgery.

Cataract surgery is followed by post-operative eye drops for a duration of 4-6 weeks. The multitude of ocular barriers, coupled with the discomfort experienced by both the patient and their relatives in frequently administering eye drops, significantly undermines patient compliance, ultimately impeding the recovery of the patient. This study aimed to design and develop an ocular drug delivery system as an effort to achieve a drop-free post-operative care after cataract surgery. An implant was prepared containing a biodegradable polymer Poly-lactic-co-glycolic acid (PLGA), Dexamethasone (DEX) as an anti-inflammatory drug, and Moxifloxacin(MOX) as an antibiotic. Implant characterization and drug loading analysis were conducted. In vitro drug release profile showed that the release of the two drugs are correlated with the clinical prescription for post operative eye drops. In vivo study was conducted on New Zealand albino rabbits where one eye underwent cataract surgery, and the drug delivery implant was inserted into the capsular bag after placement of the synthetic intraocular lens (IOL). Borderline increase in the intraocular pressure (IOP) was noted in the test sample group. Slit-lamp observations revealed no significant anterior chamber reaction in all study groups. Histopathology study of the operated eye revealed no significant pathology in the test samples. This work aims at developing the intra ocular drug delivery implant which will replace the post-operative eye drops and help the patient with the post-operative hassle of eye drops.

Gelatin/O-carboxymethyl chitosan injectable self-healing hydrogels for ibuprofen and naproxen dual release.

Recently, a significantly greater clinical benefit has been reported with a combination of glucosamine sulfate and nonsteroidal anti-inflammatory drugs (NSAIDs) compared to either treatment alone for the growing osteoarthritis (OA) disease. So, this study introduces hydrogels using O-carboxymethyl chitosan (O-CMC, structurally akin glucosamine glycan), and Gelatin type A (GA) in a 1:2 ratio with ß-glycerophosphate (ßGPh) at varying percentages (5 %, 12.5 %, and 15 %). We show that hydrogel properties, adaptable for drug delivery or tissue engineering, can be fine-tuned based on OCMC:ßGPh ratio. CMC/GA/ßGPh-12.5 exhibited a swelling rate of 189 %, compressive stress of 164 kPa, and compressive modulus of 3.4 kPa. The self-healing hydrogel also exhibited excellent injectability through a 21-gauge needle, requiring only 5 N of force. Ibuprofen and Naproxen release from CMC/GA/ßGPh-12.5 and CMC/GA/ßGPh-15 of designed dimensions (bi-layer structures of different diameter and height) were measured, and drug release kinetics were estimated using mathematical equations (MATLAB and polyfit program). CMC/GA/ßGPh-12.5 demonstrated significant antibacterial effects against E. coli and S. aureus, a high cell survival rate of 89 % against L929 fibroblasts, and strong cell adhesion, all indicating biocompatibility. These findings underscore potential of these hydrogels as promising candidates for treating inflammatory diseases such as osteoarthritis.

Magnetically Actuated Helical Microrobot with Magnetic Nanoparticle Retrieval and Sequential Dual-Drug Release Abilities.

Cancer is one of the diseases with high mortality worldwide. Various methods for cancer treatment are being developed, and among them, magnetically driven microrobots capable of minimally invasive surgery and accurate targeting are in the spotlight. However, existing medical magnetically manipulated microrobots contain magnetic nanoparticles (MNPs), which can cause toxicity to normal cells after the delivery of therapeutic drugs. In addition, there is a limitation in that cancer cells become resistant to the drug by mainly delivering only one drug, thereby reducing the treatment efficiency. In this paper, to overcome these limitations, we propose a microrobot that can separate/retrieve MNPs after precise targeting of the microrobot and can sequentially deliver dual drugs (gemcitabine (GEM) and doxorubicin (DOX)). First, after the proposed microrobot targeting, MNPs attached to the microrobot surface can be separated from the microrobot using focused ultrasound (FUS) and retrieved through an external magnetic field. Second, the active release of the first conjugated drug GEM to the surface of the microrobot is possible using near-infrared (NIR), and as the microrobot slowly decomposes over time, the release of the second encapsulated DOX is possible. Therefore, it is possible to increase the cancer cell treatment efficiency with sequential dual drugs in the microrobot. We performed basic experiments on the targeting of the proposed magnetically manipulated microrobot, separation/retrieval of MNPs, and the sequential dual-drug release and validated the performances of the microrobot through in vitro experiments using the EMA/FUS/NIR integrated system. As a result, the proposed microrobot is expected to be used as one of the methods to improve cancer cell treatment efficiency by improving the limitations of existing microrobots in cancer cell treatment.

Multimodal effects of asymmetric coating of coronary stents by electrospinning and electrophoretic deposition.

Drug-eluting stents (DESs) are drug-coated vascular implants that inhibit smooth muscle cell proliferation and limit in-stent re-stenosis. However, traditional DESs release a single drug into the blood and cannot cope with complex mechanisms in atherosclerosis and body responses. The present study aimed to develop a novel multimodal stent by fabricating asymmetric coating with electrophoretic deposition and electrospinning. Herein, we use heparin-loaded alginate (Hep/Alg) and atorvastatin calcium-loaded polyurethane (AtvCa/PU) coatings on the stent luminal and abluminal surfaces, respectively. Scanning electron microscopy (SEM) micrographs showed that the alginate coatings had uniformity and thin thickness. Meanwhile, the PU fibers were formed without beads, with an acceptable diameter and suitable mechanical properties. PU nanofiber revealed minimal degradation in a 1-month study. The release of AtvCa and Hep continued for 8 days without a significant initial burst release. None of the stent coatings were cytotoxic or hemolytic, and PU nanofibers supported the survival of human umbilical endothelial cells (HUVEC) with high adhesion and flattened morphologies. The results indicate that electrophoretic deposition and electrospinning have significant potential for achieving asymmetric coating on stents and a promising approach for dual drug release for multimodal effects in vascular stent applications.

Imprinted hydrogels with LbL coating for dual drug release from soft contact lenses materials.

A combined strategy to control the release of two drugs, one anti-inflammatory (diclofenac sodium, DCF) and one antibiotic (moxifloxacin hydrochloride, MXF), from a soft contact lens (SCL) material, was assessed. The material was a silicone-based hydrogel, which was modified by molecular imprinting with MXF and coated by the layer-by-layer (LbL) method using natural polyelectrolytes: alginate (ALG), poly-l-lysine (PLL) and hyaluronate (HA), crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Imprinting was used to increase the amount of MXF loaded and to sustain its release, while the LbL coating acted as a diffusion barrier for DCF and improved the surface properties. The drugs were loaded by soaking in a DCF + MXF dual solution. High hydrostatic pressure (HHP) was successfully applied in the sterilization of the drug-loaded hydrogels. The transmittance, refractive index, wettability and ionic permeability of the hydrogels remained within the required levels for SCLs application. The concentrations of the released DCF and MXF stayed above the IC50 and the MIC (for S. aureus and S. epidermidis) values, for 9 and 10 days, respectively. No ocular irritancy was detected by the HET-CAM test. NIH/3T3 cell viability demonstrated that the drug-loaded hydrogels were not toxic, and cell adhesion was reduced.

Sequential growth factor releasing double cryogel system for enhanced bone regeneration.

Bone regeneration is a complicated physiological process regulated by several growth factors. In particular, vascular endothelial growth factor (VEGF) and bone morphogenetic protein-4 (BMP-4) are regarded as key factors that induce bone regeneration by angiogenesis and osteogenesis. In this study, we developed a double cryogel system (DC) composed of gelatin/chitosan cryogel (GC) surrounded by gelatin/heparin cryogel (GH) for dual drug delivery with different release kinetics. VEGF was loaded in GH (outer layer of DC) for the initial release of VEGF to induce angiogenesis and provide blood supply in the defect area, while BMP-4 was loaded in GC (inner layer of DC) that leads to sustained release for continuous osteogenic induction. After analyzing characteristics of the double cryogel system such as porosity, degradation rate, swelling ratio, and mechanical properties, we evaluated release kinetics of VEGF (initial release) and BMP-4 (sustained-release) by ELISA. Then, the timely release of VEGF and BMP from DC synergistically induced in vitro osteogenic differentiation as confirmed by alkaline phosphatase staining, Alizarin Red S staining, and real-time PCR analysis. Finally, a critical-sized cranial defect model confirmed the enhanced bone regeneration as a result of dual release growth factor mechanisms.

Core-sheath gelatin based electrospun nanofibers for dual delivery release of biomolecules and therapeutics.

Coaxial electrospinning with the ability to use simultaneously two separate solvents provides a promising strategy for drug delivery. Nevertheless, controlled release of hydrophilic and sensitive therapeutics from slow biodegradable polymers is still challenging. To address this gap, we fabricated core-sheath fibers for dual delivery of lysozyme, as a model protein, and phenytoin sodium as a small therapeutic molecule. The sheath was processed by a gelatin solution while the core fibers were fabricated from an aqueous gelatin/PVA solution. Microstructural studies by transmission and scanning electron microscopy reveal the formation of homogeneous core-sheath nanofibers with an outer and inner diameter of 180 ± 48 nm and 106 ± 30 nm, respectively. Thermal gravimetric analysis determines that the mass loss of the core-sheath fibers fall between the mass loss values of individual sheath and core fibers. Swelling studies indicate higher water absorption of the core-sheath mat compared to the separate sheath and core membranes. In vitro drug release studies in Phosphate Buffered Saline (PBS) determine sustained release of the therapeutics from the core-sheath structure. The release trails three stages including non-Fickian diffusion at the early stage followed by the Fickian diffusion mechanism. The present study shows a useful approach to design core-sheath nanofibrous membranes with controlled and programmable drug release profiles.

Tunable Decoupling of Dual Drug Release of Oppositely Charged, Stimuli-Responsive Anisotropic Nanoparticles.

Multicompartmentalized nanostructures are of interest because they can provide unique physicochemical properties and multifunctionalities in each compartment. Furthermore, stimuli-responsive anisotropic nanostructures (ANPs) with distinct opposite charges would be useful for drug delivery systems because different drug release kinetics could be achieved from each compartment in response to both charge and stimuli. In this study, stimuli-responsive ANPs were formed via electrohydrodynamic cojetting of poly(N-isopropylacrylamide)-based copolymers with opposite charges. The positively charged compartment consisted of poly(N-isopropylacylamide-co-stearyl acrylate-co-allylamine) (poly(NIPAM-co-SA-co-AAm)) (i.e., PNSAAm) and poly(N-isopropylacylamide-co-stearyl acrylate-co-acrylic acid) (poly(NIPAM-co-SA-co-AAc)) (i.e., PNSAAc). The two distinct compartments of ANPs were physically cross-linked through hydrophobic interactions within the copolymers. Oppositely charged, small-molecule model drugs (fluorescein sodium salt and rhodamine 6G) were separately encapsulated within each compartment and released based on changes in noncovalent interactions and temperature. Furthermore, two different biomacromolecule drugs with opposite charges, bovine serum albumin and lysozyme (which were complexed with polysaccharides by hydrophobic ion pairing), were loaded within the ANPs. Electrostatic interactions between the encapsulated drugs and each ANP compartment controlled the rate of drug release from the ANPs. In addition, these ANPs showed a thermally induced actuation, leading to drug release at different rates due to the collapse of poly(NIPAM)-based copolymers under aqueous conditions. This work may be useful for decoupled drug release kinetics.

Effect of dual-drug-releasing micelle-hydrogel composite on wound healing in vivo in full-thickness excision wound rat model.

Wound healing is a complex process involving an intricate cascade of body responses. A composite dressing that would effectively target different stages of wound healing and regeneration is urgently needed. In the current study, we tested the efficacy of a previously prepared micelle-hydrogel composite loaded with two drugs, in full-thickness excision wound model in rat. We found that the composite elicited almost no inflammation and effectively enhanced healing at all stages of the healing process. An initial burst of the first drug, amphotericin B, eliminated any preliminary infection. This burst was followed by a gradual release of curcumin as the healing and anti-inflammatory agent. Better healing was observed in rats treated with the drug-loaded composites than in blank and control groups. Wounds showed up to 80% closure in the treated group, with high collagen deposition. Re-epithelialization and granulation were also better in the treated group than in the non-treated control and blank groups. Histopathological examination revealed that drug-loaded composites improved cutaneous wound healing and regeneration. In conclusion, the micelle-hydrogel composite is an effective dressing and might have major applications in wound healing. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1094-1106, 2019.

Potential of rhBMP-2 and dexamethasone-loaded Zein/PLLA scaffolds for enhanced in vitro osteogenesis of mesenchymal stem cells.

Nanofibers fabricated by electrospinning simulate the extracellular matrix of bone cells and so researchers have taken a keen interest in them for regenerating bone tissue. The aim of this study was to fabricate ideal Zein/PLLA nanofibers by coaxial electrospinning and to load them with bone morphogenetic protein 2 (BMP-2) and dexamethasone (DEX) for dual controlled-release for bone tissue engineering applications. Morphology, surface hydrophilicity and core-shell construction were analyzed by environmental scanning electron microscopy (SEM), water contact angle and transmission electron microscopy (TEM). The properties of the scaffolds were studied in terms of the viability, morphology and osteogenic differentiation of mesenchymal stem cells (MSCs) that had been cultured on nanofiber mats of the Zein/PLLA and were determined using SEM, CCK-8 assay, quantitative ALP staining analysis, quantitative mineral deposition using Alizarin red staining (ARS), immunofluorescence staining and western blot analysis of osteogenic proteins. In vitro studies demonstrated that the biological activity of DEX and BMP-2 was retained in the dual-drug-loaded nanofiber scaffolds. A large quantity of DEX was released in the first three days, while the release of BMP-2 lasted for more than 21 days. In vitro osteogenesis studies showed that the drug-loaded nanofiber scaffolds induced osteogenic differentiation. Furthermore, the dual controlled-release of BMP-2 and DEX enhanced the osteogenic differentiation of MSCs resulting from synergistic effects. Therefore, Zein/PLLA nanofiber scaffolds loaded with BMP-2 and DEX have great potential in bone tissue engineering applications.

Micelle-Coated, Hierarchically Structured Nanofibers with Dual-Release Capability for Accelerated Wound Healing and Infection Control.

Tailoring nanofibrous matrices-a material with much promise for wound healing applications-to simultaneously mitigate bacterial colonization and stimulate wound closure of infected wounds is highly desirable. To that end, a dual-releasing, multiscale system of biodegradable electrospun nanofibers coated with biocompatible micellar nanocarriers is reported. For wound healing, transforming growth factor-ß1 is incorporated into polycaprolactone/collagen (PCL/Coll) nanofibers via electrospinning and the myofibroblastic differentiation of human dermal fibroblasts is locally stimulated. To prevent infection, biocompatible nanocarriers of polypeptide-based block copolymer micelles are deposited onto the surfaces of PCL/Coll nanofibers using tannic acid as a binding partner. Micelle-modified fibrous scaffolds are favorable for wound healing, not only supporting the attachment and spreading of fibroblasts comparable to those on noncoated nanofibers, but also significantly enhancing fibroblast migration. Micellar coatings can be loaded with gentamicin or clindamycin and exhibit antibacterial activity as measured by Petrifilm and zone of inhibition assays as well as time-dependent reduction of cellular counts of Staphylococcus aureus cultures. Moreover, delivery time of antibiotic dosage is tunable through the application of a novel modular approach. Altogether, this system holds great promise as an infection-mitigating, cell-stimulating, biodegradable skin graft for wound management and tissue engineering.

Dual drug release from hydrogels covalently containing polymeric micelles that possess different drug release properties.

In the present study, we designed hydrogels for dual drug release: the hydrogels that covalently contained the polymeric micelles that possess different drug release properties. The hydrogels that were formed from polymeric micelles possessing a tightly packed (i.e., well-entangled) inner core exhibited a higher storage modulus than the hydrogels that were formed from the polymeric micelles possessing a loosely packed structure. Furthermore, we conducted release experiments and fluorescent observations to evaluate the profiles depicting the release of two compounds, rhodamine B and auramine O, from either polymeric micelles or hydrogels. According to our results, (1) hydrogels that covalently contains polymeric micelles that possess different drug release properties successfully exhibit the independent release behaviors of the two compounds and (2) fluorescence microscopy can greatly facilitate efforts to evaluate drug release properties of materials.

Thermoresponsive nanospheres with independent dual drug release profiles for the treatment of osteoarthritis.

UNLABELLED: Dual drug delivery of drugs with different therapeutic effects in a single system is an effective way to treat a disease. One of the main challenges in dual drug delivery is to control the release behavior of each drug independently. In this study, we devised thermo-responsive polymeric nanospheres that can provide simultaneous and independent dual drug delivery in the response to temperature change. The nanospheres based on chitosan oligosaccharide conjugated pluronic F127 grafting carboxyl group were synthesized to deliver kartogenin (KGN) and diclofenac (DCF) in a single system. To achieve the dual drug release, KGN was covalently cross-linked to the outer part of the nanosphere, and DCF was loaded into the inner core of the nanosphere. The nanospheres demonstrated immediate release of DCF and sustained release of KGN, which were independently controlled by temperature change. The nanospheres treated with cold temperature effectively suppressed lipopolysaccharide-induced inflammation in chondrocytes and macrophage-like cells. The nanospheres also induced chondrogenic differentiation of mesenchymal stem cells, which was further enhanced by cold shock treatment. Bioluminescence of the fluorescence-labeled nanospheres was significantly increased after cold treatment in vivo. The nanospheres suppressed the progression of osteoarthritis in treated rats, which was further enhanced by cold treatment. The nanospheres also reduced cyclooxygenase-2 expression in the serum and synovial membrane of treated rats, which were further decreased with cold treatment. These results suggest that the thermo-responsive nanospheres provide dual-function therapeutics possessing anti-inflammatory and chondroprotective effects which can be enhanced by cold treatment. STATEMENT OF SIGNIFICANCE: We developed thermo-responsive nanospheres that can provide a useful dual-function of suppressing the inflammation and promoting chondrogenesis in the treatment of osteoarthritis. For a dual delivery system to be effective, the release behavior of each drug should be independently controlled to optimize their desired therapeutic effects. We employed rapid release of diclofenac for acute anti-inflammatory effects, and sustained release of kartogenin, a newly found molecule, for chondrogenic effects in this polymeric nanospheres. This nanosphere demonstrated immediate release of diclofenac and sustained release of kartogenin, which were independently controlled by temperature change. The effectiveness of this system to subside inflammation and regenerate cartilage in osteoarthritis was successful demonstrated through in vitro and in vivo experiments in this study. We think that this study will add a new concept to current body of knowledge in the field of drug delivery and treatment of osteoarthritis.

Double-Layered Matrix of Shellac Wax-Lutrol in Controlled Dual Drug Release.

Double-layered matrix tablets prepared from shellac wax-lutrol were fabricated using a molding technique, and the release of hydrochlorothiazide and propranolol HCl from the inner tablet or outer layer was studied. The simultaneous determination of dual drug release was measured with first derivative UV spectrophotometry. The tablet containing shellac wax as the outer tablet and lutrol as the inner tablet showed more appropriate drug release and the size of the inner layer influenced the rate of drug release. In addition, the aqueous solubility of the drug and the components of the inner tablet or outer layer affected the drug release behavior. Most of the double-layered tablets exhibited the drug-release pattern which fitted well with zero-order kinetic due to the restriction of the release surface. Biphasic drug release pattern was found in the tablet of which the outer layer rapidly eroded. The drug dissolution data from drug-loaded-outer layer could predict the dissolution time for the outer layer of drug-loaded inner part of double-layered matrix tablet. Incorporation of lutrol increased the drug release from shellac wax matrix, and the zero-order release was attained by fabricating it into a double-layered tablet.

Electrospinning of PVA/chitosan nanocomposite nanofibers containing gelatin nanoparticles as a dual drug delivery system.

Nanofibrous core-sheath nanocomposite dual drug delivery system based on poly(vinyl alcohol) (PVA)/chitosan/lidocaine hydrochloride loaded with gelatin nanoparticles were successfully prepared by the electrospinning method. Gelatin nanoparticles were prepared by nanoprecipitation and were then loaded with erythromycin antibiotic agent with the average particle size of ∼175 nm. The morphology of gelatin nanoparticles observed by field emission scanning electron microscopy (FE-SEM) was shown to be optimal at the concentration of 1.25 wt % of gelatin in aqueous phase by addition of 20 µL of glutaraldehyde 5% as the crosslinking agent. The nanoparticles were also characterized by dynamic light scattering, zeta potential measurement, and Fourier transform infrared spectroscopy (FTIR). The best bead free morphology for the PVA/chitosan nanofibrous mats were obtained at the solution weight ratio of 96/4. The nanofibrous mats were analyzed by swelling studies, FTIR and antibacterial tests. In vitro dual release profile of the core-sheath nanofibers was also studied within 72 h and showed the release efficiency equal to 84.69 and 75.13% for lidocaine hydrochloride and erythromycin, respectively. According to release exponent n, the release of lidocaine hydrochloride from the sheath part of the matrix is quasi-Fickian diffusion mechanism, while the release of erythromycin is based on anomalous or non-Fickian mechanisms.

Development of sustained and dual drug release co-extrusion formulations for individual dosing.

In personalized medicine and patient-centered medical treatment individual dosing of medicines is crucial. The Solid Dosage Pen (SDP) allows for an individual dosing of solid drug carriers by cutting them into tablet-like slices. The aim of the present study was the development of sustained release and dual release formulations with carbamazepine (CBZ) via hot-melt co-extrusion for the use in the SDP. The selection of appropriate coat- and core-formulations was performed by adapting the mechanical properties (like tensile strength and E-modulus) for example. By using different excipients (polyethyleneglycols, poloxamers, white wax, stearic acid, and carnauba wax) and drug loadings (30-50%) tailored dissolution kinetics was achieved showing cube root or zero order release mechanisms. Besides a biphasic drug release, the dose-dependent dissolution characteristics of sustained release formulations were minimized by a co-extruded wax-coated formulation. The dissolution profiles of the co-extrudates were confirmed during short term stability study (six months at 21.0 ± 0.2 °C, 45%r.h.). Due to a good layer adhesion of core and coat and adequate mechanical properties (maximum cutting force of 35.8 ± 2.0 N and 26.4 ± 2.8 N and E-modulus of 118.1 ± 8.4 and 33.9 ± 4.5 MPa for the dual drug release and the wax-coated co-extrudates, respectively) cutting off doses via the SDP was precise. While differences of the process parameters (like the barrel temperature) between the core- and the coat-layer resulted in unsatisfying content uniformities for the wax-coated co-extrudates, the content uniformity of the dual drug release co-extrudates was found to be in compliance with pharmacopoeial specification.

Ultrasound-triggered dual-drug release from poly(lactic-co-glycolic acid)/mesoporous silica nanoparticles electrospun composite fibers.

The aim of this study was to achieve on-demand controlled drug release from the dual-drug-loaded poly(lactic-co-glycolic acid)/mesoporous silica nanoparticles electrospun composite fibers by the application of ultrasound irradiation. Two drugs were loaded in different part of the composite fibrous materials, and it was found that ultrasound as an external stimulus was able to control release of drugs due to both its thermal effect and non-thermal effect. With the selective irradiation of ultrasound, the drug carrier enabled to realize controlled release, and because of different location in fibers and sensitivity of two different kinds of drugs to ultrasound irradiation, the release rate of two drugs was different. These results indicated that ultrasound irradiation was a facile method to realize the on-demand controlled release of two drugs from the electrospun fibers.