Sustained Drug Release Profile Research Articles

Parenteral platforms for tunable, long-acting administration of a highly hydrophobic antiretroviral drug

GSK2838232 (GSK8232) is a second-generation maturation inhibitor (MI) developed for the treatment of HIV with excellent broad-spectrum virological profiles. The compound has demonstrated promising clinical results as an orally administered agent. Additionally, the compound’s physical and pharmacological properties present opportunities for exploitation as long-acting parenteral formulations. Despite unique design constraints including solubility and dose of GSK8232, we report on three effective tunable drug delivery strategies: active pharmaceutical ingredient (API) suspensions, ionic liquids, and subdermal implants. Promising sustained drug release profiles were achieved in rats with each approach. Additionally, we were able to tune drug release rates through a combination of passive and active strategies, broadening applicability of these formulation approaches beyond GSK8232. Taken together, this report is an important first step to advance long-acting formulation development for critical HIV medicines that do not fit the traditional profile of suitable long-acting candidates.

A drug repurposing approach of Atorvastatin calcium for its antiproliferative activity for effective treatment of breast cancer: In vitro and in vivo assessment

Breast cancer, the most common cancer among women, caused over 500,000 deaths in 2020. Conventional treatments are expensive and have severe side effects. Drug repurposing is a novel approach aiming to reposition clinically approved non-cancer drugs into newer cancer treatments. Atorvastatin calcium (ATR Ca) which is used for the treatment of hypercholesterolemia has potential to modulate cell growth and apoptosis. The study aimed at utilizing gelucire-based solid lipid nanoparticles (SLNs) and lactoferrin (Lf) as targeting ligand to enhance tumor targeting of atorvastatin calcium for effective management of breast cancer. Lf-decorated-ATR Ca-SLNs showed acceptable particle size and PDI values <200 nm and 0.35 respectively, entrapment efficiency >90% and sustained drug release profile with 78.97 ± 12.3% released after 24 h. In vitro cytotoxicity study on breast cancer cell lines (MCF-7) showed that Lf-decorated-ATR Ca-SLNs obviously improved anti-tumor activity by 2 to 2.5 folds compared to undecorated ATR Ca-SLNs and free drug. Further, In vivo study was also carried out using Ehrlich breast cancer model in mice. Caspase-3 apoptotic marker revealed superior antineoplastic and apoptosis-inducing activity in the groups treated with ATR Ca-SLNs either decorated/ undecorated with Lf in dosage 10 mg/kg/day p < 0.001 with superior activity for lactoferrin-decorated formulation.

Cryo-Milled β-Glucan Nanoparticles for Oral Drug Delivery.

Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a novel nanoparticulate drug delivery system for the oral delivery of gemcitabine to improve its oral bioavailability. In this study, gemcitabine-loaded β-glucan NPs were fabricated using a film-casting method followed by a freezer-milling technique. As a result, the NPs showed a small particle size of 447.6 ± 14.2 nm, and a high drug entrapment efficiency of 64.3 ± 2.1%. By encapsulating gemcitabine into β-glucan NPs, a sustained drug release profile was obtained, and the anomalous diffusion release mechanism was analyzed, indicating that the drug release was governed by diffusion through the NP matrix as well as matrix erosion. The drug-loaded NPs had a greater ex vivo drug permeation through the porcine intestinal epithelial membrane compared to the plain drug solution. Cytotoxicity studies showed a safety profile of the β-glucan polymers, and the IC50s of drug solution and drug-loaded β-glucan NPs were calculated as 228.8 ± 31.2 ng·mL-1 and 306.1 ± 46.3 ng·mL-1, respectively. Additionally, the LD50 of BALB/c nude mice was determined as 204.17 mg/kg in the acute toxicity studies. Notably, pharmacokinetic studies showed that drug-loaded β-glucan NPs could achieve a 7.4-fold longer T1/2 and a 5.1-fold increase in oral bioavailability compared with plain drug solution. Finally, in vivo pharmacodynamic studies showed the promising capability of gemcitabine-loaded β-glucan NPs to inhibit the 4T1 breast tumor growth, with a 3.04- and 1.74-fold reduction compared to the untreated control and drug solution groups, respectively. In conclusion, the presented freezer-milled β-glucan NP system is a suitable drug delivery method for the oral delivery of gemcitabine and demonstrates a promising potential platform for oral chemotherapy.

Engineering of VCAM-1-targeted nanostructured lipid carriers for delivery of melatonin against acute lung injury through SIRT1/NLRP3 mediated pyroptosis signaling pathway

Acute lung injury (ALI) is a prevalent and critical condition in clinical practice. Although certain pharmacological interventions have demonstrated benefits in preclinical studies, none have been proven entirely effective thus far. Therefore, the development of more efficient treatment strategies for ALI is imperative. In this study, we prepared nanostructured lipid carriers (NLCs) conjugated with anti-VCAM-1 antibodies to encapsulate melatonin (MLT), resulting in VCAM/MLT NLCs. This approach aimed to enhance the distribution of melatonin in lung vascular endothelial cells. The VCAM/MLT NLCs had an average diameter of 364 nm, high drug loading content, and a sustained drug release profile. Notably, the NLCs conjugated with anti-VCAM-1 antibodies demonstrated more specific cellular delivery mediated by the VCAM-1 receptors, increased cellular internalization, and enhanced accumulation in lung tissues. Treatment with VCAM/MLT NLCs effectively alleviated pulmonary inflammation by activating NLRP3 inflammasome-dependent pyroptosis through up-regulation of Sirtuin 1. Our findings suggest that VCAM/MLT NLCs demonstrate remarkable therapeutic effects on ALI in both in vitro and in vivo settings, making them a promising and efficient treatment strategy for ALI.

EFFECT OF PEGYLATED POLYPROPYLENE IMINE DENDRITIC ARCHITECTURE ON PHARMACOKINETICS OF PYRAZINAMIDE ON RABBITS

Objective: This study sought to investigate the impact of pegylated polypropylene imine dendrimer-loaded pyrazinamide on drug delivery and assess this novel formulation's pharmacokinetic parameters. Methods: Various concentrations of pyrazinamide-loaded dendrimers were formulated in four distinct batches, with the most promising formulation selected for administration to New Zealand rabbits. Plasma concentrations of the drug were subsequently compared to those of the pure drug. Pharmacokinetic parameters, including maximum plasma concentration (Cmax), time to reach Cmax (tmax), the area under the curve (AUC), the area under the first moment curve (AUMC), elimination rate constant (λz), biological half-life (t1/2), and mean residence time (MRT), were meticulously determined. Results: The plasma drug concentration Vs time profile illustrated a sustained release pattern for the pyrazinamide drug-loaded dendrimer formulation compared to the pure drug. While a minor alteration was observed in peak plasma concentration, a notable divergence was noted in all other pharmacokinetic parameters. The AUC demonstrated a fourfold increase for pyrazinamide drug-loaded dendrimers, rising from 8657.94±295.10 to 34663.89±702.89 (ng/ml/h), and the mean residence time nearly doubled when compared to the pure drug. Conclusion: Pyrazinamide drug-loaded dendrimers exhibit significant potential for enhancing drug release compared to the pure drug. This novel formulation promises a substantial and sustained drug release profile, holding promise for improving therapeutic outcomes and patient compliance in the treatment of relevant conditions.

Anti-fibrotic and anti-stricture effects of biodegradable biliary stents braided with dexamethasone-impregnated sheath/core structured monofilaments

Endoscopic biliary stent insertion has been widely used for the treatment of benign biliary stricture (BBS). Thus, the development of stent materials in the perspectives of structure, mechanical properties, and biocompatibility has been also studied. However, conventional metal and plastic stents have several disadvantages, such as repeated procedures to remove or exchange them, dislodgment, restenosis, biocompatibility, and poor mechanical properties. Sustainable effectiveness, attenuation and prevention of fibrosis, and biocompatibility are key factors for the clinical application of stents to BBS treatment. In addition, loading drugs could show synergistic effects with stents’ own performance. We developed a dexamethasone-eluting biodegradable stent (DBS) consisting of a sheath/core structure with outstanding mechanical properties and sustained release of dexamethasone, which maintained its functions in a BBS duct over 12 weeks in a swine model. The insertion of our DBS not only expanded BBS areas but also healed secondary ulcers as a result of the attenuation of fibrosis. After 16 weeks from the insertion, BBS areas were totally improved, and the DBS was degraded and thoroughly disappeared without re-intervention for stent removal. Our DBS would be an effective clinical tool for non-vascular diseases. Statement of significanceThis study describes the insertion of a drug-eluting biodegradable stent (DBS) into the bile duct. The sheath/core structure of DBS confers substantial durability and a sustained drug release profile. Drug released from the DBS exhibited anti-fibrotic effects without inflammatory responses in both in vitro and in vivo experiments. The DBS maintained its function over 12 weeks after insertion into the common bile duct, expanding benign biliary stricture (BBS) and reducing inflammation to heal secondary ulcers in a swine BBS model. After 16 weeks from the DBS insertion, the DBS thoroughly disappeared without re-intervention for stent removal, resulting in totally improved BBS areas. Our findings not only spotlight the understanding of the sheath/core structure of the biodegradable stent, but also pave the way for the further application for non-vascular diseases.

Alginate-based composite scaffolds loaded with streptomycin sulfate for bone regeneration: In vitro studies

In this work, nanoceramic powders were prepared by the wet-chemical precipitation method. Furthermore, composite scaffolds were fabricated by blending alginate and gelatin with nanoceramic powders as fillers through the freeze-drying method to obtain various compositions of scaffolds, free and loaded with streptomycin sulfate. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy coupled with energy-dispersive X-ray analyses (SEM-EDX), and mechanical properties of the designed scaffolds were all investigated. The in vitro drug release was assessed with phosphate-buffered saline (PBS) at 37 °C and pH 7.4 for 28 days. In addition, kinetic drug release was characterized through mathematical models. The composite scaffold images SEM revealed porous surface morphology with variable pore sizes (113–426, 40–287 μm). The mechanical strength increased from 0.88 MPa to 4.86 MPa with the addition of higher nanoceramic content and streptomycin sulfate, while the swelling (%) decreased from 792% to 512% for the scaffolds containing fillers. In vitro bioactivity against the tested scaffolds revealed a deposition of hydroxy appetite on the scaffold's surfaces which is ensured through FTIR and SEM-EDX. The composite scaffolds revealed excellent biocompatibility, up to 90%. Also, the proliferation capability for the selected scaffolds showed increased cell populations after 48 h compared to the control. Further, the presence of streptomycin sulfate in composite scaffolds demonstrated an effective role in resisting bacterial infections with inhibition zones in a range from 10 to 22 mm as compared with the polymeric scaffolds, which had no antibacterial activity. Sustained drug release profiles from scaffolds were recorded (up to 87.96%). Overall, the results confirmed that scaffolds with (60 w/w %) of bio-nanoceramic filler in the presence of drug are the most appropriate composite scaffolds. Therefore, these developed scaffolds are a promising candidate to be used in repairing bone.

Mesoporous silica nanoparticles accommodating electrospun nanofibers as implantable local drug delivery system processed by cold atmospheric plasma and spin coating approaches

Nanofibers (NF) and nanoparticles are attractive for drug delivery to improve the drug bioavailability and administration. Easy manipulation of NF as macroscopic bulk material give rise to potential usages as implantable local drug delivery systems (LLDS) to overcome the failures of systemic drug delivery systems such as unmet personalized needs, side effects, suboptimal dosage. In this study, poly(ethylene glycol) polyethyleneimine (mPEG:PEI) copolymer blended poly ϵ-caprolactone NFs, NFblend accommodating mesoporous silica nanoparticles (MSN) as the implantable LLDS was achieved by employing spin coating and cold atmospheric plasma (CAP) as the post-process for accommodation on NFblend. The macroporous morphology, mechanical properties, wettability, and in vitro cytocompatibility of NFblend ensured their potential as an implantable LLDS and superior features compared to neat NF. The electron microscopy images affirmed of NFblend random fiber (average diameter 832 ± 321 nm) alignments and accessible macropores before and after MSN@Cur accommodation. The blending of polymers improved the elongation of NF and the tensile strength which is attributed as beneficial for implantable LLDS. CAP treatment could significantly improve the wettability of NF observed by the contact angle changes from ∼126° to ∼50° which is critical for the accommodation of curcumin-loaded MSN (MSN@Cur) and in vitro cytocompatibility of NF. The combined CAP and spin coating as the post-processes was employed for accommodating MSN@Cur on NFblend without interfering with the electrospinning process. The post-processing aided fine-tuning of curcumin dosing (∼3 µg to ∼15 µg) per dose unit and sustained zero-order drug release profile could be achieved. Introducing of MSN@Cur to cells via LLDS promoted the cell proliferation compared to MSN@Cur suspension treatments and assigned as the elimination of adverse effects by nanocarriers by the dosage form integration. All in all, NFblend-MSN@Cur was shown to have high potential to be employed as an implantable LLDS. To the best of our knowledge, this is the first study in which mPEG:PEI copolymer blend NF are united with CAP and spin coating for accommodating nano-drug carriers, which allows for NF both tissue engineering and drug delivery applications.

Synthesis of Titanate Nanotube for Antibacterial and Tissue Regeneration Applications

An increasingly crucial therapeutic issue revolves around treating bacterial infections in chronic skin wounds that have developed resistance to antibiotics. Despite the current advancements in diagnosis, a significant number of patients still experience therapeutic failure of anti-microbials or antibiotic treatments. In this study, sodium titanate nanotubes (Na-TiNTs) were synthesized via a straightforward hydrothermal approach to facilitate the immobilization of Gentamicin (Gn) and Phenytoin (PhT). The samples were extensively characterized using different techniques, including XRD, FTIR, SEM/EDX, TEM, TGA, and BET. The result reveals that synthesized Na-TiNTs are highly porous rods in shape, with an internal diameter of 5 nm and an outer diameter ranging from 10 to 15 nm. After 16 h of encapsulation, Gn had an encapsulation efficiency (EE%) of 80 ± 2.3 %, while PhT had 89.0 ± 3.1 %. Also, Gn and PhT were released linearly, reaching 95.3 ± 1.6 % and 97.3 ± 1.6 % after 96 h. The highest doses of Gn/Na-TiNTs and PhT/Na-TiNTs, about 500 mg/mL, reduced the cell viability value from 98.2 ± 2.2 % for the untreated cell to 85.1 ± 1.6 % and 88.3 ± 3.4 %, respectively. In addition, PhT/Na-TiNTs ZOI was 28.1 ± 2.3 and 30.1 ± 1.7 mm, andthe ZOI of Gn/Na-TiNTs was 39.0 ± 1.6 mm 45.0 ± 2.4 mm for S. aureus and E. coli, indicating that PhT had antibacterial potency comparable to the standard antibiotic but less than Gn/Na-TiNTs. In vitro wound closure of approximately 87 % for Gn/Na-TiNTs and exhibited a 95 % for PhT/Na-TiNTs after 72 h. The initial findings indicate that Gn/Na-TiNTs and PhT/Na-TiNTs exhibit a sustained drug release profile, which holds potential as a viable strategy for enhancing the antibacterial efficacy and promotewound healing.

Targeted co-delivery of FOXM1 aptamer and DOX by nucleolin aptamer-functionalized pH-responsive biocompatible nanodelivery system to enhance therapeutic efficacy against breast cancer: in vitro and in vivo.

Targeted nanodelivery systems offer a promising approach to cancer treatment, including the most common cancer in women, breast cancer. In this study, a targeted, pH-responsive, and biocompatible nanodelivery system based on nucleolin aptamer-functionalized biogenic titanium dioxide nanoparticles (TNP) was developed for targeted co-delivery of FOXM1 aptamer and doxorubicin (DOX) to improve breast cancer therapy. The developed targeted nanodelivery system exhibited almost spherical morphology with 124.89 ± 12.97 nm in diameter and zeta potential value of - 23.78 ± 3.66 mV. FOXM1 aptamer and DOX were loaded into the nanodelivery system with an efficiency of 100% and 97%, respectively. Moreover, the targeted nanodelivery system demonstrated excellent stability in serum and a pH-responsive sustained drug release profile over a period of 240 h following Higuchi kinetic and Fickian diffusion mechanism. The in vitro cytotoxicity experiments demonstrated that the targeted nanodelivery system provided selective internalization and strong growth inhibition effects of about 45 and 51% against nucleolin-positive 4T1 and MCF-7 breast cancer cell lines. It is noteworthy that these phenomena were not observed in nucleolin-negative cells (CHO). The preclinical studies revealed that a single-dose intravenous injection of the targeted nanodelivery system into 4T1-bearing mice inhibited tumor growth by 1.7- and 1.4-fold more efficiently than the free drug and the non-targeted nanodelivery system, respectively. Our results suggested that the developed innovative targeted pH-responsive biocompatible nanodelivery system could serve as a prospectively potential platform to improve breast cancer treatment.

Nanotextured and drug loaded Neovius Ti6Al4V ELI scaffolds with osteogenesis and anti-cancer potential

IntroductionThe use of Ti6Al4V for orthopedic implants though widely accepted, is 10X stiffer than bone, that leads to stress shielding and aseptic loosening. Further, oral delivery demands significantly large dosage of drugs. To address these twin challenges, we have fabricated open cell porous scaffolds capable of sustained dual drug delivery. Drug delivery from open cell porous Ti6Al4V implants is a promising approach for in situ delivery in orthopedic and dental implant applications. MethodologyIn this study, selective laser melting technology was used to fabricate open cell porous Ti6Al4V ELI scaffolds of 50 % volume fractions with Neovius architecture (NOCL). Electrochemical anodization was used to create micro and nano scale surface features for efficient drug loading. The two payloads: an osteogenic agent (Baicalein) and an anti-cancerous drug (Paclitaxel) were then loaded to different levels for differential release. An osteogenic agent was loaded in the nano reservoirs while paclitaxel was mixed with poloxamer and coated over the scaffold. ResultsThe mechanical stiffness of the designed NOCL lattices is approximately 1.29 ± 0.05 GPa, which is comparable to the human bone. This helps to reduce stress shielding effect. The scaffolds loaded with baicalein and paclitaxel yielded a sustained drug release profiles, releasing 57 % and 79 % of the pharmaceuticals over a 7-day period, respectively. Additionally, the baicalein-loaded nano reservoirs promote osteoblast differentiation in mesenchymal stem cells. As a result, bio-inspired 3D-printed open cell porous titanium scaffolds loaded with dual drugs offer a workable solution to the problems associated with orthopedic implants.

Fabrication and characterization of fish gelatin-based magnetic nanocomposite for biomedical applications.

Bionanocomposite is considered an advanced way to bridge the gap between the structural and functional material and achieve the desired properties in the nanocomposite. This present study highlighted the synthesis of fish gelatin-based magnetic nanocomposite (GMNC) using three different concentrations of gelatin (6% w/v, G12% w/v, and 18% w/v) individually, through the in situ coprecipitation method. The effect of gelatin concentration on the structural, functional, magnetic properties, and biocompatibility of the GMNC was studied successfully. This variation reduces the crystallite size from 20.8 to 12.2nm. GMNC obtained at minimum gelatin concentration (6% w/v) produced well-dispersed sphere-shaped magnetite nanoparticles with an average particle size of 33nm without aggregation. All three reported superparamagnetic behavior at 293K. It also noted the highly biocompatible and biodegradable nature of GMNC with a high magnetic response at a low magnetic field. This study reported the perspective of this functionalization method for biomedical applications, as GMNC is a potential carrier material that is easily attached to drug molecules through the free functional residues of gelatin molecules. The present study also performed the in vitro drug release behavior of 5'Fluorouracil-loaded GMNC (GF) at physiological conditions (pH 7.4 and 37°C). It indicates the prepared GF exhibits a sustained drug-release profile for up to 48h. Hence, these results strongly supported that the functionalized GMNC would be a potential carrier material for advanced drug delivery applications.

Synergism and attenuation of triptolide through prodrug engineering combined with liposomal scaffold strategy to enhance inhibition in pancreatic cancer

The prognosis of pancreatic cancer (PCa) is extremely poor because of its resistance to conventional therapies. Many previous studies have demonstrated that triptolide (TPL) has a potent tumoricidal activity on PCa. However, the clinical application of TPL in tumor therapy has been greatly limited by its poor aqueous solubility, short half-time, high toxicity and inefficient delivery. Here, through the engineering of prodrug technology combined with the nanodrug-delivery system (NDDS) strategy, we modified the main active site of TPL C14-OH by esterification reaction to obtain a highly lipophilic prodrug, and then encapsulated the drug in a phospholipid bilayer in liposomal vehicles through the thin-film hydration method for efficient delivery. A delivery system based on TPL lignocerate liposomes (TPL-LA-lip) for drug loading for targeted therapy against PCa was established. Our results showed that TPL-LA demonstrates exceptional compatibility with the phospholipid layer of liposomes, thereby enhancing drug retention in liposomal vehicle and improving tumor targeting and cellular uptake. Moreover, The system of TPL-LA-lip exhibited a sustained drug release profile in vitro, and intravenous administration significantly impedes tumor progression while reducing the toxicity of TPL in the PCa mouse model. These results demonstrated that the prodrug-loaded liposomes could significantly reduce the toxicity of TPL and enhance the biosafety. Overall, this prodrug approach is a simple and effective method to transform the highly toxic TPL into a safe and efficacious nanomedicine with excellent in vivo tolerability for PCa treatment.

Gelatin microsphere-alginate hydrogel combined system for sustained and gastric targeted delivery of 5-fluorouracil

In the current study, novel gelatin microspheres/methacrylated alginate hydrogel combined system (5-FU-GELms/Alg-MA) was developed for gastric targeted delivery of 5-fluorouracil as an anticancer agent. While water-in-oil emulsification method was used for the production of 5-FU-GELms, Alg-MA was synthesized through methacrylation reaction occurred by epoxide ring-opening mechanism. Then, 5-FU-GELms/Alg-MA hydrogel system was fabricated by the encapsulation of 5-FU-GELms into Alg-MA hydrogel network via UV-crosslinking. To evaluate applicability of fabricated 5-FU-GELms/Alg-MA as gastric targeted drug delivery vehicle, both swelling and in vitro drug release experiments were carried out at pH 1.2 medium resembling gastric fluid. Compared to drug release directly from 5-FU-GELms, 5-FU-GELms/Alg-MA hydrogel system showed more controlled and sustained drug release profile with lower amount of cumulative release starting from early stages, since hydrogel matrix created a barrier to the diffusion of 5-FU included in microspheres. Drug release kinetic results obtained by applying various kinetic models to release data showed that the mechanism of 5-FU release from 5-FU-GELms/Alg-MA hydrogel system is controlled by Fickian diffusion. All results revealed that 5-FU-GELms/Alg-MA hydrogel integrated system could be potentially utilized as gastric targeted drug carrier to enhance therapeutic efficacy and reduce systemic side effects in gastric cancer treatments for future studies.

Controlled release, chitosan-tethered luteolin phytocubosomes; Formulation optimization to in-vivo antiglaucoma and anti-inflammatory ocular evaluation

A chitosan-coated luteolin-loaded phytocubosomal system was prepared to improve the pharmacodynamic performance of luteolin in the treatment of glaucoma and ocular inflammation after topical ocular administration. Luteolin, a potent anti-oxidant herbal drug with poor aqueous solubility, was complexed with phospholipid. The prepared phytocubosomes were coated with chitosan, producing homogenously distributed nanosized particles (258 ± 9.05 nm) with a positive charge (+49 ± 6.09 mV), improved EE% (96 %), and increased concentration of encapsulated drug to 288 μg/ml. Polarized light microscopy revealed a cubic phase. Chitosan-coated phytocubosomes showed a sustained drug release profile (38 % over 24 h) and improved anti-oxidant activity (IC50 of 32 μg/ml). Ex vivo transcorneal permeation was higher by 3.60 folds compared to luteolin suspension. Irritancy tests confirmed their safety in ocular tissues after single and multiple administrations. The pharmacodynamic studies on glaucomatous rabbit eyes demonstrated 6.46-, 3.88-, and 1.89-fold reductions in IOP of chitosan-coated phytocubosomes compared to luteolin suspension, cubosomes, and phytocubosomes, respectively. Pharmacodynamic anti-inflammatory studies revealed faster recovery capabilities of chitosan-coated phytocubosomes over other formulations. Thus, chitosan-coated phytocubosomes could be a promising ocular hybrid system for delivering herbal lipophilic drugs such as luteolin.

In vitro and in vivo characterization of Miconazole Nitrate loaded transethosomes for the treatment of Cutaneous Candidiasis

This study aimed to fabricate Miconazole Nitrate transethosomes (MCZN TESs) embedded in chitosan-based gel for the topical treatment of Cutaneous Candidiasis. A thin film hydration method was employed to formulate MCZN TESs. The prepared MCZN TESs were optimized and analyzed for their physicochemical properties including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (%EE), Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), deformability, and Transmission electron microscopy (TEM). In vitro release, skin permeation and deposition, skin irritation, antifungal assay, and in vivo efficacy against infected rats were evaluated. The optimized MCZN TESs showed PS of 224.8 ± 5.1 nm, ZP 21.1 ± 1.10 mV, PDI 0.207 ± 0.009, and % EE 94.12 ± 0.101 % with sustained drug release profile. Moreover, MCZN TESs Gel exhibited desirable pH, spreadability, and viscosity. Notably, the penetration and deposition capabilities of MCZN TESs Gel showed a 4-fold enhancement compared to MCZN TESs. Importantly, in vitro antifungal assay elaborated MCZN TESs Gel anti-fungal activity was 2.38-fold more compared to MCZN Gel. In vivo, studies showed a 1.5 times reduction in the duration of treatment MCZN TESs Gel treated animal group. Therefore, studies demonstrated that MCZN TESs could be a suitable drug delivery system with higher penetration and good antifungal potential.

4D Printable Salicylic Acid Photopolymers for Sustained Drug Releasing, Shape Memory, Soft Tissue Scaffolds.

3D printing of pharmaceuticals offers a unique opportunity for long-term, sustained drug release profiles for an array of treatment options. Unfortunately, this approach is often limited by physical compounding or processing limitations. Modification of the active drug into a prodrug compound allows for seamless incorporation with advanced manufacturing methods that open the door to production of complex tissue scaffold drug depots. Here we demonstrate this concept using salicylic acids with varied prodrug structures for control of physical and chemical properties. The role of different salicylic acid derivatives (salicylic acid, bromosalicylic allyl ester, iodosalicylic allyl ester) and linker species (allyl salicylate, allyl 2-(allyloxy)benzoate, allyl 2-(((allyloxy)carbonyl)oxy)benzoate) were investigated using thiol-ene cross-linking in digital light processing (DLP) 3D printing to produce porous prodrug tissue scaffolds containing more than 50% salicylic acid by mass. Salicylic acid photopolymer resins were all found to be highly reactive (solidification within 5 s of irradiation at λ = 405 nm), while the cross-linked solids display tunable thermomechanical behaviors with low glass transition temperatures (Tgs) and elastomeric behaviors, with the carbonate species displaying an elastic modulus matching that of adipose tissue (approximately 65 kPa). Drug release profiles were found to be zero order, sustained release based upon hydrolytic degradation of multilayered scaffolds incorporating fluorescent modeling compounds, with release rates tuned through selection of the linker species. Cytocompatibility in 2D and 3D was further demonstrated for all species compared to polycarbonate controls, as well as salicylic acid-containing composites (physical incorporation), over a 2-week period using murine fibroblasts. The use of drugs as the matrix material for solid prodrug tissue scaffolds opens the door to novel therapeutic strategies, longer sustained release profiles, and even reduced complications for advanced medicine.

Preparation and antibacterial activity of chitosan grafted cyclodextrin hydrogel loaded berberine hydrochloride using dual gelling agent

In this paper, cyclodextrin-grafted-chitosan (CD-g-CS) with different degrees of substitution (DS) was synthesized successfully by the reaction of O-p-toluenesulfonyl-β-cyclodextrin (TCD) and chitosan (CS), and a novel injectable thermosensitive hydrogel with rapid gelation was developed by physical cross-linking using dual gelling agents of αβ-glycerophosphate-sodium and hydrogen carbonate (GP-SHC). The results of 1H-NMR showed that the DS of CD-g-CS increased with the increase of TCD/CS (w/w). The influence of CD-g-CS with different DS, the concentration of SHC, and the ratio of CD-g-CS/GP-SHC (v/v) on gel time, swelling, drug release, degradation, and antibacterial activity of hydrogels prepared were studied. The results of FTIR indicated that the intermolecular interaction occurred in the hydrogel. And the hydrogel had a three-dimensional porous structure seen from SEM images. Compared with CS/GP hydrogel, the gel time of prepared hydrogel was shorter, which was less than 6 min, and the shortest gel time was 0.5 min. The prepared hydrogels had a good swelling ratio and degradable behavior. Berberine hydrochloride (BBH) was used as a model drug, and the gel showed a sustained drug release profile. In addition, the hydrogel had excellent antibacterial activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Therefore the BBH@CD-g-CS/GP-SHC hydrogels had great potential in the development of biomedical drug delivery systems and antibacterial materials.

Design, development and in vitro quantification of novel electrosprayed everolimus-loaded Soluplus®/Polyvinyl alcohol nanoparticles via stability-indicating HPLC method in cancer therapy

Everolimus (RAD001) a mammalian target of rapamycin has been hampered by poor solubility, affecting its dissolution rate, a relationship that extends to low bioavailability. Nanoparticles (NP) based on Soluplus (SOL®) and Polyvinyl alcohol (PVA) was fabricated by electrospraying (ES) for the delivery of RAD001 to improve anti-tumour efficacy. Electrospraying with established experimental conditions produced PVA-SOL®-RAD001 NP with 71 nm mean diameter, smaller particle size distribution and >90 % encapsulation efficiency. Various polymer-drug concentrations exposed to various freeze–thaw (F/T) cycles were studied for NP optimisation and to enhance its mechanical properties. The optimised NP formulation demonstrated complete encapsulation as well as a sustained and pH dependent drug release profile for in vitro release test. In addition, to specifically study the degradation profile of RAD001 and to quantify RAD001 in the fabricated NP, a new HPLC method was developed and validated. The purpose and novelty of the HPLC method was also to ensure that RAD001 can be detected at low amounts where other conventional characterisation methods are unable to detect. The developed HPLC method was accurate, precise, robust and sensitive with LOD and LOQ values of 4.149 and 12.575 μg/mL. In conclusion, the novel developed HPLC system can be applied for the quantification of different chemotherapeutic agents and the novel electrosprayed hydrogel NP is a potential drug delivery system to increase solubility and bioavailability of RAD001 in cancer therapy.

Fused Deposition Modelling 3D-Printed Gastro-Retentive Floating Device for Propranolol Hcl Tablets.

Three-dimensional printing has revolutionized drug manufacturing and has provided a solution to the limitations associated with the conventional manufacturing method by designing complex drug delivery systems with customized drug release profiles for personalized therapies. The present investigation aims to design a gastric floating tablet with prolonged gastric floating time and sustained drug release profile. In the present study, a gastro retentive floating device (GRFD) was designed and fabricated using a fused deposition modelling (FDM)-based 3D printing technique. This device acts as a multifunctional dosage form exhibiting prolonged gastric retention time and sustained drug release profile with improved oral bioavailability in the upper gastrointestinal tract. Commercial polyvinyl alcohol (PVA) and polylactic acid (PLA) filaments were used to design GRFD, which was comprised of dual compartments. The outer sealed compartment acts as an air-filled chamber that imparts buoyancy to the device and the inner compartment is filled with a commercial propranolol hydrochloride immediate-release tablet. The device is designed as a round-shaped shell with a central opening of varying size (1 mm, 2 mm, 3 mm, and 4 mm), which acts as a drug release window. Scanning electron microscope (SEM) images were used to determine morphological characterization. The in vitro buoyancy and drug release were evaluated using the USP type II dissolution apparatus. All the designed GRFDs exhibit good floating ability and sustained drug release profiles. GRFDs fabricated using PLA filament show maximum buoyancy (>24 h) and sustained drug release for up to 10 h. The floating ability and drug release from the developed devices were governed by the drug release window opening size and the filament material affinity towards the gastric fluid. The designed GRFDs show great prospects in modifying the drug release characteristics and could be applied to any conventional immediate-release product.