Influence of type of vehicle on dermal penetration efficacy of hydrophilic, amphiphilic, lipophilic model drugs.

The influence of the vehicle on the dermal penetration efficacy of three different active ingredient (AI) surrogates (hydrophilic, amphiphilic, lipophilic model drugs), that were incorporated into these vehicles, was investigated with the ex vivo porcine ear model, which allowed to assess time and space resolved dermal penetration profiles of the AI. Fifteen different vehicles, including classical vehicles (hydrogel, oleogel, o/w cream, w/o ointment, amphiphilic cream) and innovative vehicles were included into the study. Results show tremendous differences in the penetration efficacy of the AI among the different vehicles. The differences in the total amounts of penetrated AI between lowest and highest penetration were about 3-fold for the hydrophilic AI surrogate, 3.5-fold for the amphiphilic AI and almost 5-fold for the lipophilic AI. The penetration depth was also affected by the type of vehicle. Some vehicles allowed the AI to penetrate only into the upper layers of the stratum corneum, whereas others allowed the penetration of the AI into deeper layers of the viable dermis. Data therefore demonstrate that the vehicles in compounding medications cannot be exchanged against each other randomly if a constant and safe medication is desired. The data obtained in the study provide first information on which types of vehicles are exchangeable and which types of vehicles can be used for enhanced dermal penetration of AI, thus providing a first base for a science-based selection of vehicles that can provide both, efficient dermal drug delivery and skin barrier function maintenance/strengthening at the same time.

Optimization of entrapment efficiency and release of clindamycin in microsponge based gel.

The aim of the present study was to formulate clindamycin (CLN) as a microsponge based gel to release the drug in a controlled manner and reduce the side effects in the treatment of acne. Since this method requires poor water solubility of the drug to be loaded in particles, therefore, conversion of the hydrochloride salt to free base was done. By using an emulsion solvent diffusion method, we made six different formulations of microsponges containing CLN-free base by changing the proportions of polymer, emulsifier and the pH of the external phase. These formulations were studied for physical characterization and for drug- polymer interactions. The physical characterization showed that microsponge formulations coded by C5, C6 resulted in a better loading efficiency and production yield and their particle size was less than 30 µm. Scanning electron microscopy images showed the microsponges porous and spherical. C5, C6 microsponge formulation was prepared as gel in Carbopol and in vitro evaluated. The microsponge formulation gel C8 was found to be optimized. C8 released 90.38% of drug over 12 h and showed viscosity 20,157 ± 38 cp, pH of 6.3 ± 0.09 and drug content of 99.64 ± 0.04%. Fourier transform infrared spectroscopy and differential scanning calorimetry confirmed no significant interactions between excipients and drug.

An overview on the advantages and limitations of 3D printing of microneedles.

The use of 3D printing (3DP) technology, which has been continuously evolving since the 1980s, has recently become common in healthcare services. The introduction of 3DP into the pharmaceutical industry particularly aims at the development of patient-centered dosage forms based on structure design. It is still a new research direction with potential to create the targeted release of drug delivery systems in freeform geometries. Although the use of 3DP technology for solid oral dosage forms is more preferable, studies on transdermal applications of the technology are also increasing. Microneedle sequences are one of the transdermal drug delivery (TDD) methods which are used to bypass the minimally invasive stratum corneum with novel delivery methods for small molecule drugs and vaccines. Microneedle arrays have advantages over many traditional methods. It is attractive with features such as ease of application, controlled release of active substances and patient compliance. Recently, 3D printers have been used for the production of microneedle patches. After giving a brief overview of 3DP technology, this article includes the materials necessary for the preparation of microneedles and microneedle patches specifically for penetration enhancement, preparation methods, quality parameters, and their application to TDD. In addition, the applicability of 3D microneedles in the pharmaceutical industry has been evaluated.

An in vitro visual study of fugitive aerosols released during aerosol therapy to an invasively ventilated simulated patient.

COVID-19 can cause serious respiratory complications resulting in the need for invasive ventilatory support and concurrent aerosol therapy. Aerosol therapy is considered a high risk procedure for the transmission of patient derived infectious aerosol droplets. Critical-care workers are considered to be at a high risk of inhaling such infectious droplets. The objective of this work was to use noninvasive optical methods to visualize the potential release of aerosol droplets during aerosol therapy in a model of an invasively ventilated adult patient. The noninvasive Schlieren imaging technique was used to visualize the movement of air and aerosol. Three different aerosol delivery devices: (i) a pressurized metered dose inhaler (pMDI), (ii) a compressed air driven jet nebulizer (JN), and (iii) a vibrating mesh nebulizer (VMN), were used to deliver an aerosolized therapeutic at two different positions: (i) on the inspiratory limb at the wye and (ii) on the patient side of the wye, between the wye and endotracheal tube, to a simulated intubated adult patient. Irrespective of position, there was a significant release of air and aerosol from the ventilator circuit during aerosol delivery with the pMDI and the compressed air driven JN. There was no such release when aerosol therapy was delivered with a closed-circuit VMN. Selection of aerosol delivery device is a major determining factor in the release of infectious patient derived bioaerosol from an invasively mechanically ventilated patient receiving aerosol therapy.

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening pipeline and in-vitro validation assays.

SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2'-O-MT. For virtual screening, energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard (Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs and investigational molecules (n = 5903). The screening was performed against viral targets using three sequential docking modes (i.e., HTVS, SP, and XP). Virtual screening identified ∼290 potential inhibitors based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. The resulting top eight hits were tested for their SARS-CoV-2 anti-viral activity in-vitro. Among these, a known inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), was found to be a potent inhibitor of SARS-CoV-2. Further, target validation through enzymatic assays confirmed 3CLpro to be the target. This is the first study that has showcased BIM IX as a COVID-19 inhibitor thereby validating our pipeline.

Usability Assessment of an Innovative Device in Infusion Therapy: A Mix-Method Approach Study.

Background: Flushing a venous access device is an important procedure to maintain their patency and prevent malfunctioning and complications. An innovative double-chamber syringe was developed, allowing for the assessment of catheter patency, drug delivery and final flush. This study aims to assess the usability of this new device, considering three development stages (concept, semi-functional prototype, functional prototype). Methods: An iterative methodology based on a mix-method design (qualitative and quantitative) enabled the assessment of the devices' usability by their primary end-users. A usability questionnaire was developed and applied, along with focus groups and individual interviews to nurses. Results: The usability questionnaire integrated 42 items focused on four dimensions (usefulness; ease of use; ease of learning; satisfaction and intention to use). The initial psychometric findings indicate a good internal consistency and the conceptual relevance of the items. The scores seem to be sensitive to the usability evaluation of the medical devices in different stages of product development (with lower values on functional prototype evaluation), and related to nurses' perceptions about functional and ergonomic characteristics. Conclusions: Quantitative and qualitative data provided a comprehensive overview of the double-chamber syringes' usability from the nurses' point of view, informing us of features that must be addressed.

Statistical Considerations in Assessing In Vivo Adhesion with Transdermal and Topical Delivery Systems for New Drug Applications.

Proper adhesion plays a critical role in maintaining a consistent, efficacious, and safe drug delivery profile for transdermal and topical delivery systems (TDS). As such, in vivo skin adhesion studies are recommended by regulatory agencies to support the approval of TDS in new drug applications (NDAs). A draft guidance for industry by the US Food and Drug Administration outlines a non-inferiority comparison between a test product and its reference product for generic TDS in abbreviated new drug applications (ANDAs). However, the statistical method is not applicable for evaluating adhesion of TDS for NDAs, because no reference product exists. In this article, we explore an alternative primary endpoint and a one-sided binomial test to evaluate in vivo adhesion of TDS in NDAs. Statistical considerations related to the proposed approach are discussed. To understand its potential use, the proposed approach is applied to data sets of in vivo adhesion studies from selected NDAs and ANDAs.

A painful lesson from the COVID-19 pandemic: the need for broad-spectrum, host-directed antivirals.

While the COVID-19 pandemic has spurred intense research and collaborative discovery worldwide, the development of a safe, effective, and targeted antiviral from the ground up is time intensive. Therefore, most antiviral discovery efforts are focused on the re-purposing of clinical stage or approved drugs. While emerging data on drugs undergoing COVID-19 repurpose are intriguing, there is an undeniable need to develop broad-spectrum antivirals to prevent future viral pandemics of unknown origin. The ideal drug to curtail rapid viral spread would be a broad-acting agent with activity against a wide range of viruses. Such a drug would work by modulating host-proteins that are often shared by multiple virus families thereby enabling preemptive drug development and therefore rapid deployment at the onset of an outbreak. Targeting host-pathways and cellular proteins that are hijacked by viruses can potentially offer broad-spectrum targets for the development of future antiviral drugs. Such host-directed antivirals are also likely to offer a higher barrier to the development and selection of drug resistant mutations. Given that most approved antivirals do not target host-proteins, we reinforce the need for the development of such antivirals that can be used in pre- and post-exposure populations.

Optimizing ophthalmic delivery of a poorly water soluble drug from an aqueous in situ gelling system.

Poorly soluble drugs are often unsuitable to incorporate in ocular in situ gelling systems due to the aqueous based gelling formulations and low volumes administered. For such formulations to be successful, the administered drug must have sufficient solubility to diffuse from the formulation to the eye and should not affect the gelation of the in situ gelling material. Drug salt forms can improve the solubility of poorly soluble drugs, however, as in situ gel forming formulations are often designed to be crosslinked by salts (present the lacrimal fluid) it can make salt forms difficult to formulate. The aim of this study was to develop an in situ gel forming ophthalmic formulation of a poorly soluble drug flurbiprofen (FBP) through cyclodextrin complex formation and to analyse the impact on gelation, release and permeation through the cornea. Hydroxypropyl-beta-cyclodextrin (HßCD) was used as a complexing agent and low acyl gellan gum was added to the FBP- HßCD complex as a water soluble in situ gelling polymer. Measurements were performed using rheo-dissolution, which utilises a rheometer with a modified lower plate that has the unique ability to allow rheological measurement and analysis of drug release simultaneously. An ex-vivo permeation study was also performed using porcine cornea. Rheological measurements in terms of elastic (G') and viscous (G″) modulus showed rapid gelation of the formulation upon contact with simulated lacrimal fluid (SLF). Approximately, 97% FBP was released when 10% HßCD was used and release was decreased to 79% when the amount of HßCD was increased to 20%. The percentage of drug permeation through the cornea was 55% in 300 min whereas the marketed non gelling eye drop formulation containing FBP sodium showed only 37% permeation. The data presented here, revealed that not only could a poorly soluble drug be complexed with cyclodextrin and loaded into an in situ gelling system without interfering with the gelation, but also permeability the of the drug improved.

The allergic eye: recommendations about pharmacotherapy and recent therapeutic agents.

PURPOSE OF REVIEW: Ocular allergies affect an estimated 40% of the population, 98% of which are because of allergic conjunctivitis. With the current advent of both repurposed drugs for ocular allergies, as well as novel drugs and methods of administration, there is a need for an updated review of current available medications. A clear characterization of each treatment will ultimately allow treating physicians to restore patients' quality of life and decrease burden of disease. RECENT FINDINGS: Currently, there are a number of reformulated antihistamines, with cetrizine being the most recent ophthalmic solution available. Nevertheless, there is ongoing research in the field of immunotherapy, steroids, flavonoids, cannabis, and drug-delivery systems. SUMMARY: Although dual-activity agents remain the keystone for treatment, newer drugs and drug-delivery systems offer other novel directions for delivering appropriate relief with minimal adverse effects.

Practical strategies for a safe and effective delivery of aerosolized medications to patients with COVID-19.

The COVID-19, the disease caused by a novel coronavirus and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly across the globe. It has caused outbreaks of illness due to person-to-person transmission of the virus mainly via close contacts and droplets produced by an infected person's cough or sneeze. Exhaled droplets from infected patients with COVID-19 can be inhaled into the lungs and leads to respiratory illness such as pneumonia and acute respiratory distress syndrome. Although aerosol therapy is a mainstay procedure used to treat pulmonary diseases at home and healthcare settings, it has a potential for fugitive emissions during therapy due to the generation of aerosols and droplets as a source of respiratory pathogens. Delivering aerosolized medications to patients with COVID-19 can aggravate the spread of the novel coronavirus. This has been a real concern for caregivers and healthcare professionals who are susceptible to unintended inhalation of fugitive emissions during therapy. Due to a scarcity of information in this area of clinical practice, the purpose of this paper is to explain how to deliver aerosolized medications to mild-, sub-intensive, and intensive-care patients with COVID-19 and how to protect staff from exposure to exhaled droplets during aerosol therapy.

Ultrasound-mediated therapies for the treatment of biofilms in chronic wounds: a review of present knowledge.

Bacterial biofilms are an ever-growing concern for public health, featuring both inherited genetic resistance and a conferred innate tolerance to traditional antibiotic therapies. Consequently, there is a growing interest in novel methods of drug delivery, in order to increase the efficacy of antimicrobial agents. One such method is the use of acoustically activated microbubbles, which undergo volumetric oscillations and collapse upon exposure to an ultrasound field. This facilitates physical perturbation of the biofilm and provides the means to control drug delivery both temporally and spatially. In line with current literature in this area, this review offers a rounded argument for why ultrasound-responsive agents could be an integral part of advancing wound care. To achieve this, we will outline the development and clinical significance of biofilms in the context of chronic infections. We will then discuss current practices used in combating biofilms in chronic wounds and then critically evaluate the use of acoustically activated gas microbubbles as an emerging treatment modality. Moreover, we will introduce the novel concept of microbubbles carrying biologically active gases that may facilitate biofilm dispersal.

Design of a Drug-Eluting Subcutaneous Implant of the Antiretroviral Tenofovir Alafenamide Fumarate.

PURPOSE: Sexual transmission of HIV has been clinically proven to be preventable with a once-daily oral tablet; however, missed doses dramatically increase the risk of HIV infection. Long-acting subcutaneous implants do not allow the user to miss a dose. A desirable long-acting drug-eluting implant can deliver a constant amount of drug, adjust the delivered dose, and be readily manufactured. We present a long-acting, subcutaneous implant design composed of tenofovir alafenamide hemifumarate (TAF) pellets loaded in a sealed polyether urethane tube for the prevention of HIV transmission. METHODS: Implants were prepared with pressed drug pellets and extruded polyurethane tubing. In vitro release rate of implants using different pellet formulations, rate-controlling membranes, and geometries were measured. RESULTS: Tenofovir alafenamide release appeared to be governed by a pseudo-steady state and followed a mass transport model of release from a cylindrical drug reservoir. Implant seal integrity was tested and confirmed using mechanical testing. The inclusion of sodium chloride in the pellet increased the release rate and reduced initial lag. The release was sustained for 100 days. CONCLUSIONS: The release rate of tenofovir alafenamide mechanistically varied with geometry and rate controlling membrane composition. The polyether urethane implant presented herein is modular and tunable to adjust the release rate and duration of the TAF release.

Low-frequency dual-frequency ultrasound-mediated microbubble cavitation for transdermal minoxidil delivery and hair growth enhancement.

Ultrasound (US) has been found to rejuvenate and invigorate the hair follicles, increase the size of hair shafts, and promote new hair growth. Our present study found that dual-frequency US-mediated microbubble (MB) cavitation significantly enhanced minoxidil (Mx) delivery in both in vitro and in vivo models, while increasing the hair growth efficacy compared to single-frequency US sonication. The in vitro experiments showed that cavitation activity was enhanced more significantly during dual-frequency sonication than single-frequency sonication in higher concentration of MBs. The pigskin penetration depth in the group in which dual-frequency US was combined with MBs was 1.54 and 2.86 times greater than for single-frequency US combined with MBs and in the control group, respectively; the corresponding increases in the release rate of Mx at 18 hours in in vitro Franz-diffusion-cell experiments were 24.9% and 43.7%. During 21 days of treatment in C57BL/6J mice experiments, the growth rate at day 11 in the group in which dual-frequency US was combined with MBs increased by 2.07 times compared to single-frequency US combined with MBs. These results indicate that dual-frequency US-mediated MB cavitation can significantly increase both skin permeability and transdermal drug delivery. At the same US power density, hair growth was greater in the group with dual-frequency US plus MBs than in the group with single-frequency US plus MBs, without damaging the skin in mice.

Vaginal Polyelectrolyte Layer-by-Layer Films Based on Chitosan Derivatives and Eudragit® S100 for pH Responsive Release of Tenofovir.

Women are still at high risk of contracting the human immunodeficiency virus (HIV) virus due to the lack of protection methods under their control, especially in sub-Saharan countries. Polyelectrolyte multilayer smart vaginal films based on chitosan derivatives (chitosan lactate, chitosan tartate, and chitosan citrate) and Eudragit® S100 were developed for the pH-sensitive release of Tenofovir. Films were characterized through texture analysis and scanning electron microscopy (SEM). Swelling and drug release studies were carried out in simulated vaginal fluid and a mixture of simulated vaginal and seminal fluids. Ex vivo mucoadhesion was evaluated in bovine vaginal mucosa. SEM micrographs revealed the formation of multilayer films. According to texture analysis, chitosan citrate was the most flexible compared to chitosan tartrate and lactate. The swelling studies showed a moderate water uptake (<300% in all cases), leading to the sustained release of Tenofovir in simulated vaginal fluid (up to 120 h), which was accelerated in the simulated fluid mixture (4-6 h). The films had high mucoadhesion in bovine vaginal mucosa. The multilayer films formed by a mixture of chitosan citrate and Eudragit® S100 proved to be the most promising, with zero toxicity, excellent mechanical properties, moderate swelling (<100%), high mucoadhesion capacity, and Tenofovir release of 120 h and 4 h in vaginal fluid and the simulated fluid mixture respectively.

Nanoparticle Drug Delivery Can Reduce the Hepatotoxicity of Therapeutic Cargo.

Hepatotoxicity is a key concern in the clinical translation of nanotherapeutics because preclinical studies have consistently shown that nanotherapeutics accumulates extensively in the liver. However, clinical-stage nanotherapeutics have not shown increased hepatotoxicity. Factors that can contribute to the hepatotoxicity of nanotherapeutics beyond the intrinsic hepatotoxicity of nanoparticles (NPs) are poorly understood. Because of this knowledge gap, clinical translation efforts have avoided hepatotoxic molecules. By examining the hepatotoxicity of nanoformulations of known hepatotoxic compounds, it is demonstrated that nanotherapeutics are associated with lower hepatotoxicity than their small-molecule counterparts. It is also found that the reduced hepatotoxicity is related to the uptake of nanotherapeutics by macrophages in the liver. These findings can facilitate further development and clinical translation of nanotherapeutics.

Use of a Predictive Regression Model for Estimating Hold-Up Volume for Biologic Drug Product Presentations.

A drug delivery system is designed to administer a therapeutic dose according to its label claim. Upon delivery of a parenteral drug product, the volume remaining inside the container that cannot be extracted at the end of drug administration is called the hold-up volume (HUV) and is primarily considered product wastage. To meet the label claim, every drug product container is filled with a slight excess volume. For early-stage products in clinical phase, for which material availability is often a limitation, excess volume in drug product containers has to be determined experimentally using several grams of product. In such scenarios, established models that can predict HUV in primary drug product containers would be valuable for product development. The objective of this study was to determine HUV with 95% confidence intervals across various container closures and drug delivery systems by using aqueous PEG 400 solution mimicking the viscosity of biologic drug products. ISO 2R, 6R, and 10R vials and single-use hypodermic syringes attached to a Luer lock needle (25 gauge, 1½ in.) were used to mimic parenteral drug product container and delivery systems for determination of HUV. Glass prefilled syringes in 1 mL and 2.25 mL configurations were also used to determine HUV with 95% confidence intervals. A linear regression model was developed for determination of HUV as a function of viscosity and as a function of container closure and a needle-based delivery system. This model predicting HUV was confirmed by using monoclonal antibodies of varying formulations and viscosities for container closure and delivery systems tested in this study. The model provided here can be used to determine HUV for a particular container closure for a drug solution with known viscosity that can subsequently be used to evaluate fill volume specifications and label claim for a dosage form.

Optimizing Aerosolization Using Computational Fluid Dynamics in a Pediatric Air-Jet Dry Powder Inhaler.

The objective of this study was to optimize the performance of a high-efficiency pediatric inhaler, referred to as the pediatric air-jet DPI, using computational fluid dynamics (CFD) simulations with supporting experimental analysis of aerosol formation. The pediatric air-jet DPI forms an internal flow pathway consisting of an inlet jet of high-speed air, capsule chamber containing a powder formulation, and outlet orifice. Instead of simulating full breakup of the powder bed to an aerosol in this complex flow system, which is computationally expensive, flow-field-based dispersion parameters were sought that correlated with experimentally determined aerosolization metrics. For the pediatric air-jet DPI configuration that was considered, mass median aerodynamic diameter (MMAD) directly correlated with input turbulent kinetic energy normalized by actuation pressure and flow kinetic energy. Emitted dose (ED) correlated best with input flow rate multiplied by the ratio of capillary diameters. Based on these dispersion parameters, an automated CFD process was used over multiple iterations of over 100 designs to identify optimal inlet and outlet capillary diameters, which affected system performance in complex and unexpected ways. Experimental verification of the optimized designs indicated an MMAD < 1.6 µm and an ED > 90% of loaded dose. While extrathoracic depositional loss will be determined in future studies, at an operating flow rate of 15 L/min, it is expected that pediatric mouth-throat or even nose-throat aerosol deposition fractions will be below 10% and potentially less than 5% representing a significant improvement in the delivery efficiency of dry powder pharmaceutical aerosols to children.

Enhanced anti-tumor immunotherapy by dissolving microneedle patch loaded ovalbumin.

The skin is a very suitable organ for the induction of immune responses to vaccine antigens. Antigen delivery systems to the skin by needle and syringe directly deposit the antigen into the epidermal-dermal compartment, one of the most immunocompetent sites due to the presence of professional antigen-presenting cells aimed at the induction of antigen-specific T cells. In this study, we analyzed the amount of ovalbumin as an antigen delivered to the skin by a microneedle. When ovalbumin protein as an antigen was delivered to the skin of mice using a dissolving microneedle, it induced an immune response through the enhanced proliferation and cytokines production by the splenocytes and lymph nodes. Also, it effectively increased the ovalbumin-specific CD8+ T cell and CD4+ T cell population and induced an ovalbumin-specific CTL response against the graft of ovalbumin-expressing EG7 tumor cells in the immunized mice. Also, we identified the inhibition of tumor growth and prevention of tumor formation in the context of the therapeutic and prophylactic vaccine, respectively through EG-7 tumor mouse model. Finally, these data show the potential of patches as attractive antigen delivery vehicles.