Sustained Release Drug Delivery Research Articles

Scope and Application of Hot Melt Extrusion in the Development of Controlled and Sustained Release Drug Delivery Systems.

Controlled-release drug delivery systems (CRDDS) are more beneficial than conventional immediate release (IRDDS) for reduced intake, prolonged duration of action, lesser adverse effects, higher bioavailability, etc. The preparation of CRDDS is more complex than IRDDS. The hot melt extrusion (HME) technique is used for developing amorphous solid dispersion of poorly water soluble drugs to improve their dissolution rate and oral bioavailability. HME can be employed to develop CRDDS. Sustained release delivery systems (SRDDS), usually given orally, can also be developed using HME. This technique has the advantages of using no organic solvent, converting crystalline drugs to amorphous, improving bioavailability, etc. However, the heat sensitivity of drugs, miscibility between drug-polymer, and the availability of a few polymers are some of the challenges HME faces in developing CRDDS and SRDDS. The selection of a suitable polymer and the optimization of the process with the help of the QbD principle are two important aspects of the successful application of HME. In this review, strategies to prepare SRDDS and CRDDS using HME are discussed with its applications in research.

Quantitative analysis of loxoprofen sodium loaded microspheres comprising pectin and its thiolated conjugates: In-vivo evaluation of their sustained release behavior

Continuous use of oral NSAIDs can damage mucosal membrane, which results in decreased bioavailability and non-compliance with the therapy. But the use of sustained release drug delivery systems might offer a solution. Objective was to synthesize mucoadhesive SR microspheres by using different combinations of pectin (PEC) and its thiolated derivative (T-PEC3100) for improved loxoprofen (LS) permeation. Thiolated pectin (T-PEC) was synthesized by the esterification method using thioglycolic acid. Thiolation was confirmed by thiol group quantification and charring point determination. Further characterization was done by Fourier Transform Infrared spectroscopy (FTIR), and Scanning electron microscopy (SEM). Ex-vivo mucoadhesion study was performed to confirm the improved characteristics. Microspheres (MS) were prepared using different ratios of PEC/T-PEC by solvent evaporation method and their particle size and surface morphology were evaluated. Mucus permeation study was carried out using the trans-well plate method. Sustained release behavior of prepared microspheres was investigated through the edema inhibition method in albino rats. T-PEC3100 was considered the optimum formulation for further evaluation and contained maximum thiol group content. FTIR spectra showed a characteristic peak of –SH and charring point was also changed considerably confirming the successful thiolation of PEC. SEM results showed spherical microspheres in the size range of 2–10 μm. Thiol-rich formulation of MS exhibited more than 80 % release after 12 h and maximum absorbable dose (MAD) was calculated as 400 μg % inhibition of edema in MS treated group was slowly attained initially but the reduction in inflammation was detected even after 24 h as compared to control group. Promising results from In-vivo edema inhibition study suggest the possible use of these thiolated MS in formulating sustained release formulation for arthritis.

Polystyrene Sulfonate Resin as an Ophthalmic Carrier for Enhanced Bioavailability of Ligustrazine Phosphate Controlled Release System

Topical ocular sustained-release drug delivery systems represent an effective strategy for the treatment of ocular diseases, for which a suitable carrier has yet to be sufficiently developed. Herein, an eye-compatible sodium polystyrene sulfonate resin (SPSR) was synthesized with a uniform particle size of about 3 μm. Ligustrazine phosphate (LP) was adsorbed to SPSR by cation exchange to form LP@SPSR. LP@SPSR suspension eye drops were further developed using the combination of Carbopol 934P and xanthan gum as suspending agents. The LP@SPSR suspension showed a sustained release in vitro, which was consistent with the observed porcine corneal penetration ex vivo. Pharmacokinetics in tear fluid of rabits indicated that LP@SPSR suspension led to prolonged ocular retention of LP and a 2-fold improved the area under the drug concentration-time curve (AUC0-t). Pharmacokinetics in the aqueous humor of rabbits showed 2.8-fold enhancement in the AUC0-t compared to LP solution. The LP@SPSR suspension exhibited no cytotoxicity to human corneal epithelial cells, nor irritation was observed in rabbit eyes. Thus, the LP@SPSR suspension has been validated as a safe and sustained release system leading to enhanced ophthalmic bioavailability for treating ocular diseases.

Enhancing osteoporosis treatment using a targeted, sustained-release drug delivery system based on macrocyclic amphiphile

Osteoporosis, a prevalent systemic bone metabolic disorder, primarily affects postmenopausal women and is characterized by increased bone fragility and a heightened risk of fractures. The efficacy of current osteoporosis treatments is often limited by non-specific drug targeting and undesirable off-target skeletal side effects. To address this challenge, we have developed a novel hydroxyapatite-responsive drug delivery system. This system utilizes a self-assembled p-phosphonatocalix[4]arene tetradodecyl ether (PC4A12C), engineered to specifically target and sustain the release of osteoporosis medication at sites of bone remodeling. Our focus centers on icariin (ICA), a drug known for its potent osteogenic properties and minimal adverse effects. In vitro, ICA-loaded PC4A12C (ICA@PC4A12C) demonstrated enhanced proliferation, differentiation, and mineralization in bone marrow mesenchymal stem cells (BMSCs). In vivo, ICA@PC4A12C exhibited superior efficacy in specifically targeting bone tissue, ensuring a controlled and slow release of icariin directly within the bone environment. In an osteoporosis mouse model, treatment with ICA@PC4A12C showed notable enhancement in osteogenic activity and a significant increase in bone density compared to ICA alone. These results demonstrate the potential of PC4A12C as an effective drug carrier in the development of advanced antiosteoporotic drug delivery systems.

Sustained-release drug delivery systems.

The design and development of a sustained-release drug delivery system targeting the administration of active pharmaceutical ingredients (APIs) to the eye could overcome the limitations of topically administered eye drops. Understanding how to modify or design new materials with specific functional properties that promote the attachment and release of specific drugs over longer time periods, alongside understanding clinical needs, can lead to new strategic opportunities to improve treatment options. In this paper we discuss two approaches to the design or modification of materials to produce a sustained therapeutic effect. Firstly, we discuss how the synthesis of a peptide hydrogel from a naturally-derived antimicrobial material led to the design of a bandage contact lens which may be able to be used prophylactically to reduce post-surgery infection. Secondly, we discuss how silicone oil tamponade agents used to treat retinal detachments can have adjunctive behaviour to enhance the solubility of the anti-proliferative drug retinoic acid and produce a sustained release over several weeks. These studies are the result of close partnerships between clinical ophthalmologists, materials scientists, and chemists, and illustrate how these partnerships can lead to comprehensive understandings that have the potential to change patient outcomes.

A superabsorbent and pH-responsive copolymer-hydrogel based on acemannan from Aloe vera (Aloe barbadensis M.): A smart material for drug delivery

Combining natural polysaccharides with synthetic materials improves their functional properties which are essential for designing sustained-release drug delivery systems. In this context, the Aloe vera leaf mucilage/hydrogel (ALH) was reacted with acrylic acid (AA) to synthesize a copolymerized hydrogel, i.e., ALH-grafted-Polyacrylic acid (ALH-g-PAA) through free radical copolymerization. Concentrations of the crosslinker N,N′-methylene-bis-acrylamide (MBA), and the initiator potassium persulfate (KPS) were optimized to study their effects on ALH-g-PAA swelling. The FTIR and solid-state NMR (CP/MAS 13C NMR) spectra witnessed the formation of ALH-g-PAA. Scanning electron microscopy (SEM) analysis revealed superporous nature of ALH-g-PAA. The gel fraction (%) of ALH-g-PAA was directly related to the concentrations of AA and MBA whereas the sol fraction was inversely related to the concentrations of AA and MBA. The porosity (%) of ALH-g-PAA directly depends on the concentration of AA and MBA. The ALH-g-PAA swelled admirably at pH 7.4 and insignificantly at pH 1.2. The ALH-g-PAA offered on/off switching properties at pH 7.4/1.2. The metoprolol tartrate was loaded on different formulations of ALH-g-PAA. The ALH-g-PAA showed pH, time, and swelling-dependent release of metoprolol tartrate (MT) for 24 h following the first-order kinetic and Korsmeyer-Peppas model. Haemocompatibility studies ascertained the non-thrombogenic and non-hemolytic behavior of ALH-g-PAA.

Application of ultrasound-assisted compression and 3D-printing semi-solid extrusion techniques to the development of sustained-release drug delivery systems based on a novel biodegradable aliphatic copolyester

The purpose of this study was to investigate the ability of two advanced hot-processing technologies, Ultrasound-Assisted Compression (USAC) and 3D-printing Semi-solid Extrusion (SSE), to manufacture sustained-release drug delivery systems based on a novel biodegradable aliphatic copolyester. The copolymer was synthesized from ω-pentadecalactone (PDL), 1,4-cyclohexanedimethanol (CHDM) and dimethyl succinate (DMS) (monomer ratio PDL/CHDM/DMS 70/30/30) by enzymatic ring opening polymerization and two-step melt polycondensation processes and has a random microstructure, a high molecular weight (107,100 g mol−1) and a relatively low melting point (∼65 °C). The antibacterial agent metronidazole (MTZ) was chosen as model drug and binary physical mixtures copolymer:drug were prepared at 90:10 and 70:30 w/w ratios. Thermal analysis studies evidenced that the formulations could be processed below their degradation temperatures. Drug delivery devices with dense and meshed structures were manufactured using USAC and SSE techniques, respectively, with USAC devices exhibiting more reproducible physical properties than the SSE systems. Powder X-ray diffraction and scanning electron microscopy studies showed a partial sintering of the copolyester during USAC processing while MTZ remained mostly crystalline. In contrast, the copolymer melted and the drug underwent some amorphization when processed using SSE. In vitro drug release studies in phosphate buffer (pH 6.8) showed that, after an initial burst release of metronidazole, USAC and SSE devices exhibited a prolonged and/or sustained drug release over 20 days. The initial burst release was dependent on the manufacturing technique and the drug/polymer ratio, being minimized for SSE devices containing 10 wt% MTZ. The whole drug release profiles fitted well to the Peppas-Sahlin model, being drug diffusion the predominant release mechanism. After the burst release, the sustained release period of USAC and SSE devices containing 10 wt% MTZ showed a good fit to the zero-order kinetic model, with faster drug release from the SSE devices due to the larger surface area of their meshed structure. In conclusion, this work demonstrates that processing the aliphatic copolyester by both USAC and SSE technologies provides an attractive strategy to manufacture biodegradable drug delivery systems for long-term release of metronidazole.

Self-Assembled PLGA-Pluronic F127 Microsphere for Sustained Drug Release for Osteoarthritis.

For many years, sustained-release drug delivery systems (SRDDS) have emerged as a featured topic in the pharmaceutical field. Particularly for chronic diseases, such as osteoarthritis, there is a lot of demand for SRDDS because of the long treatment period and repetitive medication administration. Thus, we developed an injectable PLGA-F127 microsphere (MS) that is capable of the in situ conversion to an implant. The microprecipitation method for PLGA-F127 MS was established, and the physicochemical stability of the products was confirmed. The microspheres were assembled into a single mass in 37 °C aqueous conditions and showed a remarkably delayed drug release profile. First, the release started with no significant initial burst and lagged for 60 days. After that, in the next 40 days, the remaining 75% of the drugs were constantly released until day 105. We expect that our PLGA-F127 MS could be employed to extend the release period of 2 months of medication to 4 months. This could be a valuable solution for developing novel SRDDS for local injections.

Manufacturing and characterisation of 3D-printed sustained-release Timolol implants for glaucoma treatment.

Timolol maleate (TML) is a beta-blocker drug that is commonly used to lower the intraocular pressure in glaucoma. This study focused on using a 3D printing (3DP) method for the manufacturing of an ocular, implantable, sustained-release drug delivery system (DDS). Polycaprolactone (PCL), and PCL with 5 or 10% TML implants were manufactured using a one-step 3DP process. Their physicochemical characteristics were analysed using light microscopy, scanning electronic microscopy (SEM), differential scanning calorimetry (DSC) / thermal gravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). The in vitro drug release was evaluated by UV-spectrophotometry. Finally, the effect of the implants on cell viability in human trabecular meshwork cells was assessed. All the implants showed a smooth surface. Thermal analysis demonstrated that the implants remained thermally stable at the temperatures used for the printing, and FTIR studies showed that there were no significant interactions between PCL and TML. Both concentrations (5 & 10%) of TML achieved sustained release from the implants over the 8-week study period. All implants were non-cytotoxic to human trabecular cells. This study shows proof of concept that 3DP can be used to print biocompatible and personalised ocular implantable sustained-release DDSs for the treatment of glaucoma.

A neutrophil elastase inhibitor, sivelestat, attenuates sepsis-induced acute kidney injury by inhibiting oxidative stress

BackgroundSivelestat, a selective inhibitor of neutrophil elastase (NE), can mitigate sepsis-related acute lung injury. However, the role of sivelestat in inhibiting oxidative stress and attenuating sepsis-related acute kidney injury (AKI) remains unclear. Here, we reported the effects of sivelestat against oxidative stress-induced AKI by suppressing the production of oxidative stress indicators. Materials and methodsA male Sprague-Dawley rat model of sepsis was established by cecal ligation and puncture (CLP). Sivelestat or normal saline was administered into jugular vein with a sustained-release drug delivery system. Indicators of inflammation and AKI, including white blood cells (WBC), neutrophils, lymphocytes, C-reactive proteins (CRP), procalcitonin (PCT), blood urea nitrogen (BUN), creatinine (Cr) and uric acid (UA), were assessed at 24 h post-sivelestat treatment. Indicators of liver injury, including direct bilirubin (DBIL), indirect bilirubin (IBIL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), were also assessed at 24 h post-sivelestat treatment. Indicators of oxidative stress, including superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), were assessed at 12 h and 24 h post-sivelestat treatment. At 24 h post-sivelestat treatment, H&E staining of kidney and liver tissue was performed to observe pathological alterations. ResultsAt 24 h post normal saline or sivelestat (0.2 g/kg body weight) treatment, WBC, neutrophil, CRP, PCT, MDA, BUN, Cr, UA, AST, ALT, DBIL and IBIL were increased, while SOD and GSH-Px were decreased, in septic rats treated with normal saline compared with that in non-septic rats treated with normal saline (all p < 0.05). The changes of these indicators were reversed in septic rats treated with sivelestat compared with that in septic rats treated with normal saline (all p < 0.05). Similar results were found regarding the levels of oxidative stress indicators at 12 h post-sivelestat treatment. The degenerative histopathological changes in both kidney and liver tissues were ameliorated upon sivelestat treatment. ConclusionsSivelestat plays a protective role in sepsis-related AKI by inhibiting oxidative stress. Our study reveals a possible therapeutic potential of sivelestat for oxidative stress-induced AKI.

Construction and in vitro/in vivo evaluation of menantine hydrochloride oral liquid sustained-release drug delivery system

Objective The purpose of the present study was to formulate a menantine hydrochloride (MH) sustained-release suspension. Methods Menantine hydrochloride drug resin complex (MH-DRC) was prepared with strong acid cation exchange resin as carrier using water bath method. The MH-DRC was characterized using scanning electron microscopy, X-ray diffraction and infrared spectroscopy. The MH-coated microcapsule (MH-CM) with optimized formulation was further dispersed in a suitable medium to obtain a sustained-release suspension. The rats were given both the MH sustained-release suspension and the commercial MH sustained-release capsule by intragastric administration. The plasma concentration-time curves and related pharmacokinetic parameters were also investigated using a non-atrioventricular model. Results MH and ion-exchange resin were ionically bonded. AmberliteIRP®69 had a higher affinity for MH at the initial concentration of 5 mg·mL−1 and a reaction temperature of 25.0 ± 0.5 °C. In vitro drug release profile showed that both the drug resin complex and the coated microcapsules had a certain level of sustained-release effect. The t1/2 of MH sustained-release suspension was extended from 68.44 h to 72.79 h with the peak blood concentration being decreased to 3.56 μg·mL−1 and the Tmax extended to 12 h compared with the commercial MH sustained-release capsule. The concentration-time curve of the self-made MH sustained-release suspension was flattened and the average relative bioavailability (Fr ) was 116.65% compared with the commercial MH sustained-release capsules. Conclusions The findings showed that the MH sustained-release suspension was successfully formulated with acceptable pharmacokinetic indices for effective treatment of Alzheimer’s disease.

Colon-targeted 3D-Printed mesalamine tablets: Core-shell design and in vitro/ex-vivo evaluation

ObjectivesThe present study is intended to develop a shell-core tablet using a hot melt extrusion (HME)-based dual-nozzle fused deposition modeling (FDM) three-dimensional (3D) printing approach. The primary objective was to establish a sustained-release colonic drug delivery system and improve mesalamine's permeability by incorporating Vitamin E TPGS as a permeation enhancer. MethodThe study utilized Kollidon® SR for sustained release, L-100, and HPMC HME L100 for the tablet's protective shell. Six filament formulations were tested, and the mechanical properties of the shell filaments, including the three-point bending, Hooke's law, and stiffness, were assessed. Drug release profiles of the tablets were evaluated using the USP-II dissolution apparatus, and permeability characteristics were gauged using the non-everted intestinal sac method. Solutions containing 5% w/v mesalamine and 2.5% w/v Vitamin E TPGS were employed, with pure mesalamine as a control. ResultsOptimal filament ratios were identified as 50:50 for the core and 30:70 for Eudragit L-100 to HPMC HME L100 for the shell. The resulting tablets achieved a prolonged drug release of up to 24 h for the core. They ensured minimal drug release in the upper gastrointestinal tract (∼5% in the first 5 h), effectively targeting the colon. Incorporating Vitamin E TPGS led to a 3.6-fold increase in mesalamine absorption compared to the control, and the addition of Kollidon® SR notably improved the flow properties of Mesalamine powder. ConclusionIn conclusion, this innovative approach has the potential to achieve a colon-specific drug delivery system.

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.

Preparation of polypeptide-metal complexes-coated Hosenkoside A and its inhibitory effect in cervical cancer

We reported the anti-cervical cancer effect of proprietary saponin content from seeds of Impatiens balsamina L., Hosenkoside A. Our study found that Hosenkoside A significantly promotes cell apoptosis and cell cycle arrest after administration, exhibiting anti-tumor effects. Then the transcriptome sequencing results after administration showed that Hosenkoside A had a significant inhibitory effect on Histone deacetylase 3 (HDAC3). After sufficient administration time, the inhibition of HDAC3 expression level leads to a significant decrease in lysine acetylation at histone 3 sites 4 and 9, blocking the activation of Signal transducer and activator of transcription 3 (STAT3) and achieving anti-tumor effects. In addition, we encapsulated Hosenkoside A into polypeptide metal complexes (PMC) to form slow-release spheres. This material breaks down in the tumor environment, not only does it solve the problem of low drug solubility, but it also achieves targeted sustained-release drug delivery. Under the same concentration of stimulation, the PMC complex group showed better anti-tumor effects in both in vitro and in vivo experiments.

FORMULATION, DEVELOPMENT, AND EVALUATION OF OCUSERTS FOR QUINOLONE ANTIBIOTICS

Ophthalmic films are the best sustained-release ocular drug delivery system. The present study targets developing such ocular films of antibacterial with corticosteroid and evaluating its potential. Conventional ocular dosage forms have low bioavailability with low therapeutic response. The solvent cast method employed in ophthalmic films has triggered the minds of researchers to design sustained drug delivery systems overcoming pre-corneal constraints. The compatibility of antibacterial with Loteprednol Etabonate added polymers, excipients were evaluated through preformulation studies. Different combinations of ocular inserts with antibacterial drug and corticosteroid, excipients were formulated and evaluated. Formula CLE 80 (Ciprofloxacin Hydrochloride with Loteprednol Etabonate) fulfilled the needs of all organoleptic parameters like appearance, texture, surface pH, drug content, and in-vitro studies. The results predicted CLE 80 ophthalmic film would be a promising controlled-release formulation for better patient compliance

Citric acid cross-linking of a hydrogel from Aloe vera (Aloe barbadensis M.) engenders a pH-responsive, superporous, and smart material for drug delivery.

The current research work is based on the evaluation of a citric acid (CA) cross-linked Aloe vera (Aloe barbadensis M.) leaf hydrogel (CL-ALH) for pH-dependent and sustained drug release application. The CA was used in different concentrations (1.25, 2.5, 5.0, and 10.0%) to cross-link the ALH using homogenous reaction conditions. The synthesis of CL-ALH was confirmed through Fourier transform and nuclear magnetic resonance spectroscopic studies. The thermal analysis indicated that the ALH and CL-ALH were stable and decomposed in two steps. The scanning electron microscopic images of CL-ALH confirmed its porous nature due to the presence of interconnected channeling. The swelling of CL-ALH was evaluated at pH 1.2, 6.8, and 7.4 as well as in deionized water (DW). High swelling of CL-ALH was observed in DW, and at pH 7.4 and 6.8 whereas, less swelling of CL-ALH was witnessed at pH 1.2. CL-ALH also exhibited swelling/deswelling behavior in DW and ethanol, DW and normal saline, and at pH 7.4 and 1.2. Tablets were prepared from CL-ALH as a release retarding agent demonstrating the sustained release of venlafaxine hydrochloride (VFX) for 8 h. Whereas, VFX was released within 4 h from the ALH-based tablet formulation (un-cross-linked material) indicating the prolonged and sustained release behavior of CL-ALH. The VFX was released from CL-ALH tablets and followed zero-order kinetics. The mechanism followed by VFX release from CL-ALH tablets was non-Fickian diffusion. The in vivo fate of the tablet formulation was observed through an X-ray study. The CL-ALH-based tablet safely passed through the stomach of a stray dog without any significant erosion and then disintegrated in the small intestine and colon. These findings confirmed that the CL-ALH is an effective excipient for designing a sustained-release drug delivery system for the small intestine and colon.

A comprehensive review on sustained release tablets

Sustained release is a method to reduce therapeutic drugs side effects by preventing the therapeutic concentration of the drug from fluctuating in the body. Sustained release is used to describe a pharmaceutical dosage form formulated to retard the release of therapeutic drug so that it remains in the systemic circulation for prolonged time and its plasma profile is sustained in duration. Sustained release drug delivery system has been formulated in form of tablets to slow down release of drug from tablets. It works on various mechanisms to control the release rate of drugs. Formulation approaches that have been utilized are drug dissolution, drug diffusion, matrix erosion. Present review work deals with the different aspect of the sustained release tablets.

Injectable long-acting ivacaftor-loaded poly (lactide-co-glycolide) microparticle formulations for the treatment of cystic fibrosis: In vitro characterization and in vivo pharmacokinetics in mice

Optimizing a sustained-release drug delivery system for the treatment of cystic fibrosis (CF) is crucial for decreasing the dosing frequency and improving patients’ compliance with the treatment regimen. In the current work, we developed an injectable poly(D,L-lactide-co-glycolide) (PLGA) microparticle formulation loaded with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that increases the open probability of the CFTR anion channel, using a single emulsion solvent evaporation technique. We aimed to study the effect of different parameters on the characteristics of the prepared formulations to select an optimized microparticle formulation to be used in an in vivo pharmacokinetic study in mice. First, a suite of ivacaftor-loaded microparticles were prepared using different formulation parameters in order to study the effect of varying these parameters on microparticle size, morphology, drug loading, encapsulation efficiency, and in vitro release profiles. Prepared microparticles were spherical with diameters ranging from 1.91–6.93 µm, percent drug loading (% DL) of 3.91–10.3%, percent encapsulation efficiencies (% EE) of 26.6–100%, and an overall slow cumulative release profile. We selected the formulation that demonstrated optimal combined % DL and % EE values (8.25 and 90.7%, respectively) for further studies. These microparticles had an average particle size of 6.83 µm and a slow tri-phasic in vitro release profile (up to 6 weeks). In vivo pharmacokinetic studies in mice showed that the subcutaneously injected microparticles resulted in steady plasma levels of ivacaftor over a period of 28 days, and a 6-fold increase in AUC 0 – t (71.6 µg/mL*h) compared to the intravenously injected soluble ivacaftor (12.3 µg/mL*h). Our results suggest that this novel ivacaftor-loaded microparticle formulation could potentially eliminate the need for the frequent daily administration of ivacaftor to people with CF thus improving their compliance and ensuring successful treatment outcomes.

Alternatives to Topical Glaucoma Medication for Glaucoma Management.

Topical glaucoma medications have favorable safety and efficacy, but their use is limited by factors such as side effects, nonadherence, costs, ocular surface disease, intraocular pressure fluctuations, diminished quality of life, and the inherent difficulty of penetrating the corneal surface. Although traditionally these limitations have been accepted as an inevitable part of glaucoma treatment, a rapidly-evolving arena of minimally invasive surgical and laser interventions has initiated the beginnings of a reevaluation of the glaucoma treatment paradigm. This reevaluation encompasses an overall shift away from the reactive, topical-medication-first default and a shift toward earlier intervention with laser or surgical therapies such as selective laser trabeculoplasty, sustained-release drug delivery, and micro-invasive glaucoma surgery. Aside from favorable safety, these interventions may have clinically important attributes such as consistent IOP control, cost-effectiveness, independence from patient adherence, prevention of disease progression, and improved quality of life.

Engineered therapeutic proteins for sustained-release drug delivery systems.

Proteins play a vital role in diverse biological processes in the human body, and protein therapeutics have been applied to treat different diseases such as cancers, genetic disorders, autoimmunity, and inflammation. Protein therapeutics have demonstrated their advantages, such as specific pharmaceutical effects, low toxicity, and strong solubility. However, several disadvantages arise in clinical applications, including short half-life, immunogenicity, and low permeation, leading to reduced drug effectiveness. The structure of protein therapeutics can be modified to increase molecular size, leading to prolonged stability and increased plasma half-life. Notably, the controlled-release delivery systems for the sustained release of protein drugs and preserving the stability of cargo proteins are envisioned as a potential approach to overcome these challenges. In this review, we summarize recent research progress related to structural modifications (PEGylation, glycosylation, poly amino acid modification, and molecular biology-based strategies) and promising long-term delivery systems, such as polymer-based systems (injectable gel/implants, microparticles, nanoparticles, micro/nanogels, functional polymers), lipid-based systems (liposomes, solid lipid nanoparticles, nanostructured lipid carriers), and inorganic nanoparticles exploited for protein therapeutics. STATEMENT OF SIGNIFICANCE: In this review, we highlight recent advances concerning modifying proteins directly to enhance their stability and functionality and discuss state-of-the-art methods for the delivery and controlled long-term release of active protein therapeutics to their target site. In terms of drug modifications, four widely used strategies, including PEGylation, poly amino acid modification, glycosylation, and genetic, are discussed. As for drug delivery systems, we emphasize recent progress relating to polymer-based systems, lipid-based systems developed, and inorganic nanoparticles for protein sustained-release delivery. This review points out the areas requiring focused research attention before the full potential of protein therapeutics for human health and disease can be realized.