Dry Powder Formulation Research Articles

Review of Proliposomal Gel for Transdermal drug delivery system

Proliposomes are an innovative kind of carrier-mediated drug delivery that offers numerous advantages over traditional liposomes. The conventional liposomes are susceptible to oxidation or hydrolysis, as well as sedimentation, aggregation, or fusion with other substances. While, proliposomes are far more stable than liposomes, making them better suited for the delivery of pharmaceuticals. They are a dry, free-flowing, granular substance that, when it comes in touch with water or a biological fluid inside the body, instantly transforms into a liposomal dispersion. Future systems for delivering medications could be proliposomes. They have achieved a considerable improvement in resolving the stability, bioavailability, and solubility of poorly soluble medicines difficulties associated with liposomes with their non-invasive drug administration into or across the skin. They are a better alternative to the liposomal vesicular system because of their increased physical and chemical stability and potential for scalability for commercial viability. Because they are in dry powder form, they can be manufactured into unit dose forms like tablets, capsules, and beads, among other things. Because of all these advantages, proliposomes have been used for a variety of medical applications.

Performance Testing of a Homemade Aerosol Generator for Pulmonary Administration of Dry Powder Formulations to Mice.

A challenge in the development of dry powder formulations for inhalation is the poor reproducibility of their administration to small laboratory animals. The currently used devices for the pulmonary administration of dry powder formulations to small rodents often function sub-optimally as they use the same puff of air for both powder dispersion and aerosol delivery. As a result, either the air volume and flow rate are too low for complete powder deagglomeration or they are too high for effective aerosol delivery to the lungs of the animal. Therefore, novel and better devices are desired. We here present an aerosol generator designed to administer a pre-generated aerosol to the lungs of mice. By mapping the complex relationship between the airflow rate, delivery time and emitted dose, we were able to control the amount of powder being delivered from the aerosol generator. The emitted aerosol had a size range favorable for lung deposition and could be measured reproducibly. Nevertheless, in vivo fluorescent imaging still revealed considerable differences between the mice in terms of the dose deposited and the distribution of powder over the lungs, suggesting that a certain biological variation in lung deposition is inevitable.

Electrolytes in Multiple-Phase Hydrogen Storage Reactions

Multiple-phase hydrogen storage materials such as metal alanates and borohydrides, and destabilized systems offer the possibility of high hydrogen storage capacity with favorable thermodynamics. However, the multiphase nature of these materials intrinsically limits the kinetics due to the required transport of species between phases, which are typically in dry powder form. To address this limitation, the influence of added electrolytes is explored. This approach is motivated by analogy with similar multiphase battery reactions that show reduced kinetic limitations while necessarily containing electrolytes. Previous experimental results showing improved kinetics for MgH2/Sn (using a LiBH4/KBH4 eutectic electrolyte) and NaAlH4 (using a diglyme electrolyte) are further analyzed in terms of this analogy. The results show that the analogy is useful and rate constants are increased. Importantly, the inclusion of an electrolyte also appears to alleviate the continuously decreasing rates with the extent of reaction, which is characteristic of many multiphase hydrides. Instead, reaction rates are approximately constant until near completion. Together, these effects can lead to >10× shorter overall reaction times. In addition, new results are presented for the hydrogenation of MgB2 using Li/K/CsI and Li/K/CsCl eutectic electrolytes, where >60% conversion to Mg(BH4)2 was demonstrated at 350 bar.

Evaluation of the Potential for Drug-Drug Interactions with Inhaled Itraconazole Using Physiologically Based Pharmacokinetic Modelling, Based on Phase 1 Clinical Data

Itraconazole is a potent inhibitor of cytochrome P450 3A4 (CYP3A4), associated with numerous drug-drug interactions (DDI). PUR1900, a dry powder formulation of itraconazole for oral inhalation, results in high lung and low systemic exposure. This project used physiologically based pharmacokinetic (PBPK) modeling to assess the DDI potential of inhaled PUR1900, using midazolam as a “victim drug.” The basic and mechanistic static models evaluated the DDI potential of PUR1900, assuming 5 mg of midazolam coadministration at steady-state itraconazole exposure. Subsequently, Simcyp® PBPK simulation software and pharmacokinetic data from a Phase 1 clinical trial with PUR1900 (NCT03479411) were used to optimize an existing itraconazole PBPK model. The model was applied to investigate the potential for CYP3A4 DDI when 5 mg of midazolam is co-administered with inhaled PUR1900 at a steady state in a virtual healthy population at PUR1900 doses up to 40 mg per day. The basic static and mechanistic static models suggested a strong likelihood for DDI with inhaled PUR1900. The PBPK model was consistent with PUR1900 Phase 1 trial data. The geometric mean Cmax and AUC ratios of midazolam at a maximum dose of 40 mg PUR1900 were 1.14 and 1.26, respectively, indicating a minimal likelihood of DDI with inhaled PUR1900. The low systemic exposure of itraconazole when administered as PUR1900 results in minimal to no CYP3A4 inhibition, reducing the concern of drug-drug interactions. As the risk of CYP3A4 DDI is predicted to be significantly lower when itraconazole is administered via oral inhalation as PUR1900, it is likely that PUR1900 can be safely used for the treatment of pulmonary fungal infections in patients taking pharmaceuticals currently contraindicated with oral itraconazole.Graphical

Carrier-Free Inhalable Dry Microparticles of Celecoxib: Use of the Electrospraying Technique.

Upregulation of cyclooxygenase (COX-2) plays an important role in lung cancer pathogenesis. Celecoxib (CLX), a selective COX-2 inhibitor, may have beneficial effects in COVID-19-induced inflammatory storms. The current study aimed to develop carrier-free inhalable CLX microparticles by electrospraying as a dry powder formulation for inhalation (DPI). CLX microparticles were prepared through an electrospraying method using a suitable solvent mixture at two different drug concentrations. The obtained powders were characterized in terms of their morphology, solid state, dissolution behavior, and aerosolization performance. Electrosprayed particles obtained from the ethanol-acetone solvent mixture with a drug concentration of 3 % w/v exhibited the best in vitro aerosolization properties. The value of the fine particle fraction obtained for the engineered drug particles was 12-fold higher than that of the untreated CLX. When the concentration of CLX was increased, a remarkable reduction in FPF was obtained. The smallest median mass aerodynamic diameter was obtained from the electrosprayed CLX at a 3% concentration (2.82 µm) compared to 5% (3.25 µm) and untreated CLX (4.18 µm). DSC and FTIR experiments showed no change in drug crystallinity or structure of the prepared powders during the electrospraying process. The findings of this study suggest that electrospraying has potential applications in the preparation of DPI formulations.

Engineering artesunate-loaded micelles using spray drying for pulmonary drug delivery

Novel d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) micelles containing the anti-cancer drug artesunate (ART) were developed in a dry powder form for inhalation for the treatment of lung cancer. Targeted delivery to the lungs via inhalation presents a challenge, and the current study involved the development, characterization, and cytotoxicity determination of the dry powder formulations. TPGS micelles encapsulating ART were successfully prepared using thin-film hydration method, followed by the preparation of a dry powder formulation through spray-drying, which included lactose and leucine as carrier molecules. Characterization of the dry powder formulation using Sympatec laser diffraction particle size analyzer and a next generation impactor. The analysis showed a unimodal particle size distribution with a mean particle size of 3.27 μm and a fine particle fraction of 31%, respectively. Artesunate-loaded micelle dry powder formulation demonstrated higher cytotoxicity against the A549 adenocarcinomic human alveolar basal epithelial cell line when compared to currently used cancer therapies docetaxel and doxorubicin. Overall, this study demonstrates that spray-dried micelles containing artesunate have the potential to be used as a dry powder formulation for inhalation in the treatment of lung cancer.

Elucidation of the using condition and working mechanism of tertiary lactose in dry powder formulations for inhalation

Tertiary lactose has been shown to improve aerosolization performance of carrier-based dry powder inhalation formulations. The working mechanism of the tertiary lactose, however, is still unclear, even the optimal working condition of the lactose fines. Two strategies to incorporate the tertiary lactose were proposed, the “tertiary lactose-carrier-API” and “tertiary lactose-API-carrier”, to decrease the adhesiveness of the drug-carrier by forming different powder aggregates. The effects of the tertiary lactose with different sizes and mass percentages on the aerosolization performance for the two types of formulations were systemically investigated. The results showed that the smaller-sized tertiary lactose is beneficial for powder dispersion and aerosolization, which could be further improved by optimizing its concentration. In terms of the aerosolization performance, the “tertiary lactose-carrier-API” type of ternary formulations obtained highly superior aerosolization performance and significantly enhanced detachment of fine drug particles from large particles in general.

Protective immunity induced by an inhaled SARS-CoV-2 subunit vaccine

Targeting the site of infection is a promising strategy for improving vaccine effectivity. To date, licensed COVID-19 vaccines have been administered intramuscularly despite the fact that SARS-CoV-2 is a respiratory virus. Here, we aim to induce local protective mucosal immune responses with an inhaled subunit vaccine candidate, ISR52, based on the SARS-CoV-2 Spike S1 protein. When tested in a lethal challenge hACE2 transgenic SARS-CoV-2 mouse model, intranasal and intratracheal administration of ISR52 provided superior protection against severe infection, compared to the subcutaneous injection of the vaccine. Interestingly for a protein-based vaccine, inhaled ISR52 elicited both CD4 and CD8 T-cell Spike-specific responses that were maintained for at least 6 months in wild-type mice. Induced IgG and IgA responses cross-reacting with several SARS- CoV-2 variants of concern were detected in the lung and in serum and protected animals displayed neutralizing antibodies. Based on our results, we are developing ISR52 as a dry powder formulation for inhalation, that does not require cold-chain distribution or the use of needle administration, for evaluation in a Phase I/II clinical trial.

Effect of chicken by-products on the physicochemical properties of forcemeat formulations

The effect of by-products of chicken slaughter (chicken feet and heads) on the physical and chemical properties of forcemeat formulations was investigated. The chicken feet and heads were prepared in the form of ground mass and in the form of dry powder. Six types of samples were made with the addition of ground mass and powder of the chicken feet and heads in different proportions separately and together in the forcemeat formulation and the control sample without additive. Based on the results of the chemical composition study, it was found that adding the additive in powder form significantly increases the protein and ash content of the forcemeat formulations, as well as the water-binding capacity and yield stress. The addition of additive in the form of ground mass reduces the total content of protein and fat while the moisture and ash contents increase, the value of water-binding capacity decreases. According to the microstructural characteristics, there are no obvious differences between the control and experimental samples, with no large bone particles, cartilage or coarse crumpled particles. Incorporating chicken by-products into meat-based products is a beneficial approach to enhance their physical and chemical properties, leading to improved overall quality. Additionally, this method can be cost-effective and contribute to sustainability by reducing poultry waste.

WS05.02 A Phase-1 multiple ascending dose healthy volunteer study to evaluate the safety, tolerability, and pharmacokinetics of GDC-6988, a dry powder formulation of a selective inhaled potentiator of TMEM16A

Objectives: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are not indicated for ~10% of people with CF and may not fully restore CFTR function. GDC-6988 is a potent and selective potentiator of TMEM16A and is expected to enhance calcium-induced anion transport, increase airway fluid secretion, and promote mucus hydration and clearance. We previously reported outcomes in healthy volunteers with a nebulized formulation of GDC-6988. Here we present blinded outcomes from an ongoing Phase 1 study of a dry powder (DP) formulation of GDC-6988.

DOE supported optimization of biodegradable polymeric nanoparticles based dry powder inhaler for targeted delivery of afatinib in non-small cell lung cancer

Poly (lactic-co-glycolic acid) (PLGA) based nanoparticles are increasingly being used to deliver anticancer agents directly to the lungs. This approach offers targeted delivery of the drug, which minimizes the risk of side effects associated with oral administration. Afatinib-loaded PLGA nanoparticles were fabricated with a double emulsification solvent evaporation method and optimized by a factorial design (32) approach. The optimized batch of afatinib-loaded polymeric nanoparticles exhibited suitable entrapment efficiency (78.15 ± 2.20% w/w), drug loading (3.90 ± 0.11% w/w), particle size (198.1 ± 3.5 nm), and zeta potential (−0.519 ± 0.197 mV). A dry powder-based inhaled drug delivery platform is rapid-acting, handy, and self-administered that is expected to enhance patient compliance. The lyophilization method was used to convert afatinib-loaded PLGA nanoparticles into dry powder form. The formulated afatinib-loaded PLGA nanoparticles dry powder inhaler (PLGA NDPI) demonstrated good flow properties with 77.86 ± 3.02% drug content and 6.883 ± 0.369 μm particle size distribution. With more than 85% of the dosage released from an inhaler device in the eight-stage cascade impactor through an in-vitro lung deposition investigation, the particles also proved their capacity to penetrate the deeper area of the lung. Further, the in-vitro drug release study demonstrated more than 80% drug release from PLGA NDPI at different pH of phosphate buffer solutions. A549 adenocarcinoma cell line cytotoxicity investigation revealed that PLGA NDPI has a stronger potential for suppressing tumour cell proliferation than pure drug solution. Fluorescein isothiocyanate (FITC) encapsulated afatinib PLGA NDPI formulation was more effectively absorbed intracellularly by adenocarcinoma cells than plain FITC dye. Taken together, the results suggest that, the formulated afatinib PLGA NDPI can be a promising approach for targeted lung delivery of the anticancer agent.

A comprehensive overview of dry powder inhalers for pulmonary drug delivery: Challenges, advances, optimization techniques, and applications

Dry powder inhaler (DPI) is an attractive dosage form for local and systemic pulmonary drug delivery. However, designing DPIs with adequate physicochemical properties is challenging. The development of novel pulmonary drug delivery systems requires the selection of suitable particle engineering techniques, carriers, and excipients. In addition, optimization of physico-chemical properties of such systems is critical for their efficient delivery and drug release. This review highlights the recent advances in the field of inhalable dry powder formulations with a special emphasis on the current particle engineering techniques, challenges in the development of novel pulmonary drug delivery systems, selection of a suitable carrier and excipients, and the evaluation of factors impacting aerosolization. Lastly, the review also discusses the current and emerging applications of DPIs for local and systemic drug delivery.

Cu, Zn- Superoxide dismutase liposomal dry powder formulations production using supercritical CO2-assisted spray-drying: A proof-of-concept

Enzyme-based inhalable therapeutics for lung inflammation are gaining interest as an alternative to long-term corticosteroids treatments. However, enzymes have poor pharmacokinetics. Encapsulating enzymes in liposomes can increase their half-live and modify their biodistribution. But both liposomes and enzymes are susceptible to destabilization during storage. This drawback can be surpassed, by converting liposomal suspension into solid dosage forms for different administration routes, including inhalation. In this study, Cu, Zn- superoxide dismutase (SOD) was encapsulated in liposomes, then dried using supercritical CO2-assisted spray-drying to make SOD-loaded liposomal dry powder formulations (SOD_Lip-DPFs). Upon resuspension in water, liposomes maintained structural integrity, with 99% SOD encapsulation efficiency and preserved enzymatic activity. Stability studies showed that SOD_Lip-DPFs maintained liposomal and enzyme stability for 50 days at 40% relative humidity. This offers a stable and efficient delivery system for enzyme-based inhalable therapeutics.

Dry Powder Inhalation for Lung Delivery in Cystic Fibrosis.

Pulmonary drug delivery has long been used for local and systemic administration of different medications used in acute and chronic respiratory diseases. Certain lung diseases, such as cystic fibrosis, rely heavily on chronic treatments, including targeted lung delivery. Pulmonary drug delivery possesses various physiological advantages compared to other delivery methods and is also convenient for the patient to use. However, the formulation of dry powder for pulmonary delivery proves challenging due to aerodynamic restrictions and the lower tolerance of the lung. The aim of this review is to provide an overview of the respiratory tract structure in patients with cystic fibrosis, including during acute and chronic lung infections and exacerbations. Furthermore, this review discusses the advantages of targeted lung delivery, including the physicochemical properties of dry powder and factors affecting clinical efficacy. Current inhalable drug treatments and drugs currently under development will also be discussed.

Lipid-Based Inhalable Micro- and Nanocarriers of Active Agents for Treating Non-Small-Cell Lung Cancer.

Non-small-cell lung cancer (NSCLC) afflicts about 2 million people worldwide, with both genetic (familial) and environmental factors contributing to its development and spread. The inadequacy of currently available therapeutic techniques, such as surgery, chemotherapy, and radiation therapy, in addressing NSCLC is reflected in the very low survival rate of this disease. Therefore, newer approaches and combination therapy regimens are required to reverse this dismal scenario. Direct administration of inhalable nanotherapeutic agents to the cancer sites can potentially lead to optimal drug use, negligible side effects, and high therapeutic gain. Lipid-based nanoparticles are ideal agents for inhalable delivery owing to their high drug loading, ideal physical traits, sustained drug release, and biocompatibility. Drugs loaded within several lipid-based nanoformulations, such as liposomes, solid-lipid nanoparticles, lipid-based micelles, etc., have been developed as both aqueous dispersed formulations as well as dry-powder formulations for inhalable delivery in NSCLC models in vitro and in vivo. This review chronicles such developments and charts the future prospects of such nanoformulations in the treatment of NSCLC.

Inhalable Nanoparticle-based Dry Powder Formulations for Respiratory Diseases: Challenges and Strategies for TranslationalResearch.

The emergence of novel respiratory infections (e.g., COVID-19) and expeditious development of nanoparticle-based COVID-19 vaccines have recently reignited considerable interest in designing inhalable nanoparticle-based drug delivery systems as next-generation respiratory therapeutics. Among various available devices in aerosol delivery, dry powder inhalers (DPIs) are preferable for delivery of nanoparticles due to their simplicity of use, high portability, and superior long-term stability. Despite research efforts devoted to developing inhaled nanoparticle-based DPI formulations, no such formulations have been approved to date, implying a research gap between bench and bedside. This review aims to address this gap by highlighting important yet often overlooked issues during pre-clinical development. We start with an overview and update on formulation and particle engineering strategies for fabricating inhalable nanoparticle-based dry powder formulations. An important but neglected aspect in in vitro characterization methodologies for linking the powder performance with their bio-fate is then discussed. Finally, the major challenges and strategies in their clinical translation are highlighted. We anticipate that focused research onto the existing knowledge gaps presented in this review would accelerate clinical applications of inhalable nanoparticle-based dry powders from a far-fetched fantasy to a reality.

A ready-to-use dry powder formulation based on protamine nanocarriers for pulmonary drug delivery

The use of oral antibiotic therapy for the treatment of respiratory diseases as tuberculosis has promoted the appearance of side effects as well as resistance to these treatments. The low solubility, high metabolism, and degradation of drugs as rifabutin, have led to the use of combined and prolonged therapies, which difficult patient compliance. In this work, we develop inhalable formulations from biomaterials such as protamine to improve the therapeutic effect. Rifabutin-loaded protamine nanocapsules (NCs) were prepared by solvent displacement method and were physico-chemically characterized and evaluated for their dissolution, permeability, stability, cytotoxicity, hemocompatibility, internalization, and aerodynamic characteristics after a spray-drying procedure. Protamine NCs presented a size of around 200 nm, positive surface charge, and drug association up to 54%. They were stable as suspension under storage, as well as in biological media and as a dry powder after lyophilization in the presence of mannitol. Nanocapsules showed a good safety profile and cellular uptake with no tolerogenic effect on macrophages and showed good compatibility with red blood cells. Moreover, the aerodynamic evaluation showed a fine particle fraction deposition up to 30% and a mass median aerodynamic diameter of about 5 µm, suitable for the pulmonary delivery of therapeutics.

Performance and biocompatibility of a novel inhalable dry powder formulation based on hyaluronic acid intended to protect the respiratory tract mucosa

Hyaluronic acid (HA) is a key component of the respiratory mucosa. By acting as a natural moisturizer, it provides hydration to the airways. In normal conditions, high molecular weight HA molecules form viscous gels providing a protective shield against external insults. This is particularly important in the upper airways where the HA protective barrier helps to prevent environmental agents to reach the lungs. Most respiratory diseases are characterized by inflammatory processes causing degradation of HA into small fragments which reduces the HA barrier effect and increases the risk of exposure to external insults. Dry powder inhalers (DPIs) are efficient devices used to deliver therapeutic molecules in the form of dry powder to the respiratory tract. PolmonYDEFENCE/DYFESA™ is a novel formulation based on HA delivered to the airways using the PillHaler® DPI device. In this study we report the results of in vitro inhalation performances of PolmonYDEFENCE/DYFESA™ as well as its mechanism of action in human cells. We found that the product targets the upper airways and that HA molecules form a protective barrier on cell surface. Furthermore, exposure to the device is safe in animal models. The promising pre-clinical results of this study provide the bases for future clinical investigation.

Biocontrol efficacy of endophytic Trichoderma spp. in fresh and dry powder formulations in controlling northern corn leaf blight in sweet corn

Seventy-three endophytic Trichoderma spp. obtained from healthy corn leaves collected in the central and northeast parts of Thailand were evaluated for their biocontrol activity against northern leaf blight disease due to Exserohilum turcicum. Among them, T. asperellum KUFA0702, KUFA0703, T. hamatum KUFA0706, T. harzianum KUFA0710, and T. harzianum KUFA0713 showed promising biocontrol efficacy against the disease under laboratory and greenhouse conditions; thus, they were selected for control efficacy evaluation under field conditions using their fresh and dry powder formulations. The results found that the fresh formulation of each Trichoderma strain displayed better biocontrol effects than their dry formulation. In field trials, the application of fresh formulation of T. harzianum KUFA0710 displayed the best disease reduction at 55.70%, while its dry formulation caused 47.46% disease reduction followed by T. harzianum KUFA0713 at 49.92% and 43.84% disease reduction when applied as fresh and dry formulations, respectively. The antagonistic activities of Trichoderma spp. included fast growth with high competition for space and nutrients and production of antifungal crude extracts. Moreover, all Trichoderma strains showed compatibility fungicides at recommendation rate with azoxystrobin (1000 ppm) and difenoconazole + azoxystrobin (500 ppm). These fungi can serve as alternative fungicides or be combined with fungicides for integrated pest management.

Engineering of inhalable nano-in-microparticles for co-delivery of small molecules and miRNAs

In this study, novel Trojan particles were engineered for direct delivery of doxorubicin (DOX) and miR-34a as model drugs to the lungs to raise local drug concentration, decrease pulmonary clearance, increase lung drug deposition, reduce systemic side effects, and overcome multi-drug resistance. For this purpose, targeted polyelectrolyte nanoparticles (tPENs) developed with layer-by-layer polymers (i.e., chitosan, dextran sulfate, and mannose-g-polyethyleneimine) were spray dried into a multiple-excipient (i.e., chitosan, leucine, and mannitol). The resulting nanoparticles were first characterized in terms of size, morphology, in vitro DOX release, cellular internalization, and in vitro cytotoxicity. tPENs showed comparable cellular uptake levels to PENs in A549 cells and no significant cytotoxicity on their metabolic activity. Co-loaded DOX/miR-34a showed a greater cytotoxicity effect than DOX-loaded tPENs and free drugs, which was confirmed by Actin staining. Thereafter, nano-in-microparticles were studied through size, morphology, aerosolization efficiency, residual moisture content, and in vitro DOX release. It was demonstrated that tPENs were successfully incorporated into microspheres with adequate emitted dose and fine particle fraction but low mass median aerodynamic diameter for deposition into the deep lung. The dry powder formulations also demonstrated a sustained DOX release at both pH values of 6.8 and 7.4.