In Vivo Release of Zafirlukast from Electrospun Polyisobutylene-Based Fiber Mats to Reduce Capsular Contracture of Silicone Breast Prostheses.

Silicone rubber tissue expanders and breast implants are associated with chronic inflammation, leading to the formation of fibrous capsules. If the inflammation is left untreated, the fibrous capsules can become hard and brittle and lead to formation of capsular contracture. When capsular contracture occurs, implant failure and reoperation is unavoidable. Fibrous capsule formation to medical grade silicone rubber breast implants and polyisobutylene-based electrospun fiber mats attached to silicone rubber with and without an anti-inflammatory therapeutic were compared. A linear polyisobutylene (PIB)-based thermoplastic elastomer is currently applied as a polymer coating for drug release on coronary stents to reduce restenosis. Recent work has created a drug releasing electrospun fiber mat from PIB-based materials. Important to this study, poly(alloocimene-b-isobutylene-b-alloocimene) (AIBA) was electrospun with zafirlukast (ZAF). ZAF is an anti-inflammatory drug that is able to reduce capsule formation and complications to silicone breast implants. Fiber mats are advantageous for local drug delivery because of their high porosity and surface area for drug release. The chief hypothesis was that local release of ZAF from AIBA would lower inflammatory signaling and resulting capsular formation after 90 days in vivo. Electrospun AIBA mats locally released ZAF, lowering inflammation and fibrous capsule development compared to medical grade silicone rubber. Locally and orally released ZAF led to similar results, but the former had much lower concentration that highlights local delivery's therapeutic potential. Released ZAF from AIBA fiber mats mitigated inflammation and serves as an alternative to existing clinical approaches.

Optimizing Process Parameters for Controlled Drug Delivery: A Quality by Design (QbD) Approach in Naltrexone Microspheres.

The formulation of microspheres involves a complex manufacturing process with multiple steps. Identifying the appropriate process parameters to achieve the desired quality attributes poses a significant challenge. This study aims to optimize the critical process parameters (CPPs) involved in the preparation of naltrexone microspheres using a Quality by Design (QbD) methodology. Additionally, the research aims to assess the drug release profiles of these microspheres under both in vivo and in vitro conditions. Critical process parameters (CPPs) and critical quality attributes (CQAs) were identified, and a Box-Behnken design was utilized to delineate the design space, ensuring alignment with the desired Quality Target Product Profile (QTPP). The investigated CPPs comprised polymer concentration, aqueous phase ratio to organic phase ratio, and quench volume. The microspheres were fabricated using the oil-in-water emulsion solvent extraction technique. Analysis revealed that increased polymer concentration was correlated with decreased particle size, reduced quench volume resulted in decreased burst release, and a heightened aqueous phase ratio to organic phase ratio improved drug entrapment. Upon analyzing the results, an optimal formulation was determined. In conclusion, the study conducted in vivo drug release testing on both the commercially available innovator product and the optimized test product utilizing an animal model. The integration of in vitro dissolution data with in vivo assessments presents a holistic understanding of drug release dynamics. The QbD approach-based optimization of CPPs furnishes informed guidance for the development of generic pharmaceutical formulations.

An injectable, nanostructured implant for the delivery of adenosine triphosphate: towards long-acting formulations of small, hydrophilic drugs.

While long-acting injectable treatments are gaining increasing interest in managing chronic diseases, the available drug delivery systems almost exclusively rely on hydrophobic matrixes, limiting their application to either hydrophobic drugs or large and hydrophilic molecules such as peptides. To address the technological lock for long-acting delivery systems tailored to small, hydrophilic drugs such as anticancer and antiviral nucleoside/nucleotide analogues, we have synthesized and characterized an original approach with a multi-scale structure: (i) a nucleotide (adenosine triphosphate, ATP) is first incorporated in hydrophilic chitosan-Fe(III) nanogels; (ii) these nanogels are then transferred by freeze-drying and resuspension into a water-free, hydrophobic medium containing PLGA and an organic solvent, N-methyl-2-pyrrolidone. We show that this specific association allows an injectable and homogeneous dispersion, able to form in situ implants upon injection in physiological or aqueous environments. This system releases ATP in vitro without any burst effect in a two-step mechanism, first as nanogels acting as an intermediate reservoir over a week, then as free drug over several weeks. In vivo studies confirmed the potential of such nanostructured implants for sustained drug release following subcutaneous injection to mice hock, opening perspectives for sustained and targeted delivery through the lymphatic system.

Study of In Vitro and In Vivo Carbamazepine Release from Coarse and Nanometric Pharmaceutical Emulsions Obtained via Ultra-High-Pressure Homogenization.

In the past decade, pharmaceutical nanotechnology has proven to be a promising alternative for improving the physicochemical and biopharmaceutical features for conventional pharmaceutical drug formulations. The goal of this study was to develop, characterize, and evaluate the in vitro and in vivo release of the model drug carbamazepine (CBZ) from two emulsified formulations with different droplet sizes (coarse and nanometric). Briefly, oil-in-water emulsions were developed using (i) Sacha inchi oil, ultrapure water, TweenTM 80, and SpanTM 80 as surfactants, (ii) methyl-paraben and propyl-paraben as preservatives, and (iii) CBZ as a nonpolar model drug. The coarse and nanometric emulsions were prepared by rotor-stator dispersion and ultra-high-pressure homogenization (UHPH), respectively. The in vitro drug release studies were conducted by dialysis, whereas the in vivo drug release was evaluated in New Zealand breed rabbits. The results showed that nanoemulsions were physically more stable than coarse emulsions, and that CBZ had a very low release for in vitro determination (<2%), and a release of 20% in the in vivo study. However, it was found that nanoemulsions could significantly increase drug absorption time from 12 h to 45 min.

Fabrication of electroactive polypyrrole-tungsten disulfide nanocomposite for enhanced in vivo drug release in mice skin.

The present study focused on the development of electric stimuli drug release carrier based on transition metal dicgalcogenides. First, tungsten disulfide (WS2) was exfoliated and functionalized using thiol chemistry with various thiol-terminated ligands such as thioglycolic acid (TGA), mercaptosuccinic acid (MSA), and 2-ethanethiol (2ET). The exfoliated WS2 underwent non-covalent coating with an electrically conductive polypyrrole (PPy) for functionalization, of which MSA-WS2-PPy achieved the highest 5-FU (anticancer drug) loading. An electrically-stimulated drug release experiment showed that TGA-WS2-PPy achieved a higher drug release (90%) than MSA-WS2-PPy (70%) and 2ET-WS2-Ppy (35%). The TGA-WS2-PPy exhibited swelling/recombination between PPY and MSA-WS2 substrate under electrical stimulation, resulting in the highest 5-FU release. From the MTT assay result, there was no significant toxicity observed for TGA-WS2-PPy-FU on HaCaT cells, indicating the biocompatibility of TGA-WS2-PPy-FU in the absence of electrical stimulation. However, HaCaT cells died when incubated with TGA-WS2-PPy-FU under electrical stimulation. Finally, Raman mapping studies for TGA-WS2-PPy drug release in the skin of nude mice demonstrated that the carrier penetrated deeper into the skin of the mice while other systems failed to exhibit significant effects under electrical stimulation. The present study offers a novel approach in developing a non-invasive electrically-stimulated drug release system based on WS2 and an externally-controlled delivery model.

Effect of gold nanoparticles on timolol uptake and its release kinetics from contact lenses: In vitro and in vivo evaluation.

Contact lenses are ideally suited for extended drug delivery to the ocular tissues, but incorporation of any particulate system affects the critical properties of the contact lens. Timolol loading by the conventional soaking method does not significantly alter the critical properties of the contact lens. However, there are challenges of low drug loading and high burst release. This research work aimed to investigate the effect of gold nanoparticles (GNPs) on loading and its release kinetics from the contact lens using the soaking method. In one approach, GNPs were loaded into the timolol soaking solution (GNPs-SS), and in another approach, GNPs were incorporated into the contact lenses (GNPs-CL) during fabrication. The contact lenses were soaked at two different concentrations of timolol (i.e., 2 mg/ml and 4 mg/ml). Swelling and optical transmittance were not significantly affected by the presence of GNPs in the contact lenses. A significant uptake/loading of timolol using the GNPs in both the approaches was observed. The in vitro flux data showed no significant improvement in the release rate profiles of timolol when using both approaches. However, the in vivo study in the rabbit tear fluid showed high timolol concentration with the GNPs-laden contact lens at all timepoints in comparison to the soaked contact lenses without GNPs. The in vivo pharmacodynamic study in rabbits showed a 2 mmHg average fall in intraocular pressure (72 h) using the GNPs-laden contact lenses, while the soaked contact lenses without GNPs and eye drops solution (0.5 %w/v) showed 2 mmHg. The drug distribution study in the ocular tissue showed a significant improvement in the drug deposition with the GNPs-laden contact lenses in the ciliary muscle and conjunctiva. This study successfully demonstrated the potential of GNPs to enhance the uptake of drug from the drug soaking solution to treat glaucoma without compromising the critical properties of contact lens. STATEMENT OF SIGNIFICANCE: In this study, we have overcome the limitation of the conventional soaking method of low drug loading and high burst release from the contact lenses. We have investigated the effect of gold nanoparticles (GNPs) on the timolol loading and its release kinetics from the contact lenses. The study revealed the potential of GNPs to enhance the uptake of timolol from the timolol soaking solution to treat glaucoma without compromising the critical lens properties.

The availability of drug by liposomal drug delivery : Individual kinetics and tissue distribution of encapsulated and released drug in mice after administration of PEGylated liposomal prednisolone phosphate.

Lately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied. However, drug release in the tumor seems more extended than in the other tissues and the non-encapsulated drug concentration decreases more slowly in the tumor than in the liver and spleen. The spleen shows a high affinity for the uptake of encapsulated drug as well as the release of drug from the liposomes. Subsequently, released drug in the spleen, and possibly also in other tissues, is probably quickly redistributed towards the blood and other tissues. This also impairs the drug delivery effect of the liposomes. In contrast to the released drug in the central circulation, liver and spleen, the released drug concentration in the tumor remains at a fairly constant level likely due to the extended release kinetics from the liposomes. These extended release characteristics in the tumor most probably contribute to the beneficial effect. Nevertheless, it should be noted that larger released drug concentrations are formed in healthy tissues.

Engineered Cellular Uptake and Controlled Drug Delivery Using Two Dimensional Nanoparticle and Polymer for Cancer Treatment.

Two major problems in chemotherapy, poor bioavailability of hydrophobic anticancer drug and its adverse side effects causing nausea, are taken into account by developing a sustained drug release vehicle along with enhanced bioavailability using two-dimensional layered double hydroxides (LDHs) with appropriate surface charge and its subsequent embedment in polymer matrix. A model hydrophobic anticancer drug, raloxifene hydrochloride (RH), is intercalated into a series of zinc iron LDHs with varying anion charge densities using an ion exchange technique. To achieve significant sustained delivery, drug-intercalated LDH is embedded in poly(ε-caprolactone) (PCL) matrix to develop intravenous administration and to improve the therapeutic index of the drug. The cause of sustained release is visualized from the strong interaction between LDH and drug, as measured through spectroscopic techniques, like X-ray photoelectron spectroscopy, infrared, UV-visible spectroscopy, and thermal measurement (depression of melting temperature and considerable reduction in heat of fusion), using differential scanning calorimeter, followed by delayed diffusion of drug from polymer matrix. Interestingly, polymer nanohybrid exhibits long-term and excellent in vitro antitumor efficacy as opposed to pure drug or drug-intercalated LDH or only drug embedded PCL (conventional drug delivery vehicle) as evident from cell viability and cell adhesion experiments prompting a model depicting greater killing efficiency (cellular uptake) of the delivery vehicle (polymer nanohybrid) controlled by its better cell adhesion as noticed through cellular uptake after tagging of fluorescence rhodamine B separately to drug and LDH. In vivo studies also confirm the sustained release of drug in the bloodstream of albino rats using polymer nanohybrid (novel drug delivery vehicle) along with a healthy liver vis-à-vis burst release using pure drug/drug-intercalated LDHs with considerable damaged liver.

Post-use assay of vaginal rings (VRs) as a potential measure of clinical trial adherence.

Adherence measurement for microbicide use within the clinical trial setting remains a challenge for the HIV prevention field. This paper describes an assay method used for determining residual dapivirine levels in post-use vaginal rings from clinical trials conducted with the Dapivirine Vaginal Matrix Ring-004 developed by the International Partnership for Microbicides to prevent male to female HIV transmission. Post-use assay results from three Ring-004 clinical trials showed that of the 25mg drug load, approximately 4mg of dapivirine is released from the matrix ring over a 28-day use period. Data obtained by both in vitro and in vivo studies indicate that dapivirine is released according to a diffusion mechanism, as determined by conformance of both data sets to the Higuchi equation. This, coupled with the low variability associated with batch production over two manufacturing sites and 20 batches of material, provides evidence that post-use ring analysis can contribute to the assessment of adherence to ring use. Limitations of this method include the potential of intra-participant and inter-participant variability and uncertainty associated with measuring the low amount of dapivirine actually released relative to the drug load. Therefore, residual drug levels should not serve as the only direct measurement for microbicide adherence in vaginal ring clinical trials but should preferably be used as part of a multi-pronged approach towards understanding and assessing adherence to vaginal ring use.

Comparison of sequential drug release in vitro and in vivo.

Development of drug-delivery devices typically involves characterizing in vitro release performance with the inherent assumption that this will closely approximate in vivo performance. Yet, as delivery devices become more complex, for instance with a sequential drug release pattern, it is important to confirm that in vivo properties correlate with the expected "programming" achieved in vitro. In this work, a systematic comparison between in vitro and in vivo biomaterial erosion and sequential release was performed for a multilayered association polymer system comprising cellulose acetate phthalate and Pluronic F-127. After assessing the materials during incubation in phosphate-buffered saline, devices were implanted supracalvarially in rats. Devices with two different doses and with different erosion rates were harvested at increasing times post-implantation, and the in vivo thickness loss, mass loss, and the drug release profiles were compared with their in vitro counterparts. The sequential release of four different drugs observed in vitro was successfully translated to in vivo conditions. Results suggest, however, that the total erosion time of the devices was longer and that release rates of the four drugs were different, with drugs initially released more quickly and then more slowly in vivo. Many comparative studies of in vitro and in vivo drug release from biodegradable polymers involved a single drug, whereas this research demonstrated that sequential release of four drugs can be maintained following implantation. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1302-1310, 2016.

In silico mechanistic disposition and in vivo evaluation of zero-order drug release from a novel triple-layered tablet matrix.

OBJECTIVES: The purpose of this study was to formulate novel triple-layered tablet (TLT) matrices employing modified polyamide 6,10 (mPA6,10) and salted-out poly(lactic-co-glycolic acid) (s-PLGA) in an attempt to achieve stratified zero-order drug release. METHODS: mPA6,10 and s-PLGA were employed as the outer drug-carrier matrices, whereas poly(ethylene oxide) (PEO) was used as the middle-layer drug matrix. Diphenhydramine HCl, ranitidine HCl and promethazine were selected as model drugs to pre-optimize the TLT, whereas atenolol, acetylsalicylic acid and simvastatin were employed as a comparable fixed dose combination to test the TLT prototype in vitro and in vivo (Large White Pig model). A total of 17 formulations that varied in terms of polymer stoichiometry, salt addition and polymer-polymer ratios were generated using a Box-Behnken experimental design. RESULTS: The in vitro drug release analysis revealed that release from the mPA6,10 layer was relatively linear with a burst release, which upon addition of sodium sulfate was reduced. Furthermore, formulations with higher quantities of mPA6,10 provided more controlled zero-order drug release and increased the matrix hardness. The addition of PEO to the s-PLGA layer significantly reduced the initial burst release that occurred when s-PLGA was used alone. CONCLUSIONS: The formulation with a lower s-PLGA:PEO ratio displayed superior zero-order release. Relatively, linear drug release was achieved from the middle-layer. The in vivo results proved the applicability of optimized TLT formulation in a therapeutic cardiovascular drug treatment regimen.