Ternary Dry Powder Agglomerate Inhalation Formulation of Melatonin With Air Jet Mixing to Improve In Vitro And In Vivo Performance.

An improved agglomerate formulation with melatonin and fine lactose for dry powder inhalation using Turbuhaler® was developed. Co-grinding lactose with 1 % magnesium stearate prior to air jet mixing served as a key factor to improve the in vitro aerosolization and in vivo efficacy. Elevated mixing pressure facilitated the dispersion and homogenization of the cohesive mixture for even distribution of agglomerate size after spheroidization and subsequent higher emitted dose with lower variation. Magnesium stearate was employed as a tertiary component to adjust the interparticle force for better aerosolization. At optimized mixing pressure, co-grinding lactose with magnesium stearate before jet mixing displayed further improvement of fine particle fraction to 71.6 ± 3.1 %. The superior fine particle deposition efficiency contributed to rapid onset of action and a high bioavailability of 67.0 % after intratracheal administration to rats. Overall, an inhalable melatonin dry powder formulation exhibiting good aerosol property and lung deposition with clinical translation potential was developed.

Co-spray-dried poly-L-lysine with L-leucine as dry powder inhalations for the treatment of pulmonary infection: Moisture-resistance and desirable aerosolization performance.

Poly-L-lysine (PLL) is a promising candidate for the treatment of pulmonary infection with lower occurrence of drug-resistance due to its unique antibacterial mechanisms. Dry powder inhalations (DPIs) are considered as the first choice for formulating PLL to treat pulmonary infection on account of direct delivery and satisfactory stability. However, hygroscopicity of PLL limited its therapeutic effect on pulmonary infection when PLL developed into DPIs. The hygroscopicity caused two obstacles including the low drug deposition in the lower respiratory tract and undesirable aerosolization performance deterioration. In this study, PLL was co-spray-dried with L-leucine (LL) to achieve moisture-resistance and desirable aerosolization performance. The ratio of PLL and LL was optimized to obtain particles with different morphology, hygroscopicity and aerodynamic properties. The obtained PLL DPIs were suitable for inhalation with a corrugated surface formed by hydrophobic LL. The anti-hygroscopicity, aerosolization performance and rheological properties of P2 DPIs were optimal when PLL:LL = 85:15. The DPIs particles were stable after being stored at high relative humidity (60 ± 5%), and their superiority in treating pulmonary infections was also proved by in vitro and in vivo experiments. The established PLL DPIs were proved to be a feasible and desirable approach to treat pulmonary infections.

Pulmonary delivery nanomedicines towards circumventing physiological barriers: Strategies and characterization approaches.

Pulmonary delivery of nanomedicines is very promising in lung local disease treatments whereas several physiological barriers limit its application via the interaction with inhaled nanomedicines, namely bio-nano interactions. These bio-nano interactions may affect the pulmonary fate of nanomedicines and impede the distribution of nanomedicines in its targeted region, and subsequently undermine the therapeutic efficacy. Pulmonary diseases are under worse scenarios as the altered physiological barriers generally induce stronger bio-nano interactions. To mitigate the bio-nano interactions and regulate the pulmonary fate of nanomedicines, a number of manipulating strategies were established based on size control, surface modification, charge tuning and co-delivery of mucolytic agents. Visualized and non-visualized characterizations can be employed to validate the robustness of the proposed strategies. This review provides a guiding overview of the physiological barriers affecting the in vivo fate of inhaled nanomedicines, the manipulating strategies, and the validation methods, which will assist with the rational design and application of pulmonary nanomedicine.

A real-time and modular approach for quick detection and mechanism exploration of DPIs with different carrier particle sizes.

Dry powder inhalers (DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes (PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform (MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes (CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device, an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation, detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.

A bacteria-resistant and self-healing spray dressing based on lyotropic liquid crystals to treat infected post-operative wounds.

The delayed healing of infected post-operative wounds has turned into a worldwide medical problem. In the clinical treatment, effective bacterial clearance and promoted wound healing were considered as two crucial aspects. However, the effect of current dressings with antibacterial activity was limited due to the declined efficacy against antibiotic-resistant bacteria, and poor mechanical property during skin extension and compression movement. In this project, a lyotropic liquid crystal (LLC)-based bacteria-resistant and self-healing spray dressing loaded with ε-polylysine (PLL) was designed. Owing to the unique antibacterial mechanism, PLL was expected to kill antibiotic-resistant bacteria efficiently, even the "superbug" methicillin-resistant Staphylococcus aureus (MRSA). The cubic cells of LLC were applied to encapsulate PLL to improve its stability and induce a sustained release, further realizing a long-term antibacterial effect. Meanwhile, the LLC precursor (LLCP) could extend to the irregular edges of the wound, and spontaneously transited to a cubic phase gel once exposed to physiological fluid. This 3D structure was also endowed with mechanically responsive viscoelasticity that formed a robust and flexible defense for wounds. An excellent antibacterial activity with more than 99% MRSA killed in 3 h was demonstrated by a killing kinetics study. The long-term effect was also proved by measuring the bacteriostatic circle test within 48 h. In addition, the unique sol-gel phase transition behavior and superior self-healing capacity of PLL-LLCP was verified with the rheological study and self-recoverable conformal deformation test in vivo. In the infected post-operative wound model, satisfactory bacterial clearance and prominent wound healing promotion were realized by PLL-LLCP, with the survival of the bacteria at lower than 0.1% and the wound closure at higher than 90%. Thus, PLL-LLCP was believed to be an excellent candidate for the therapy of infected post-operative wounds.

Oleophylic Nanospheres Self-Assembly by Emulsion Technique Utilizing the Automatic Nanoscalar Interfacial Alternation (ANIAE).

BACKGROUND: The administration of many pharmaceutical active ingredients is often performed by the injection of an aqueous-based solution. Numerous active ingredients are however, insoluble in water, which complicates their administration and restricts their efficacy. OBJECTIVE: The current solutions are hindered by both, a time-consuming manufacturing process and unsuitability for hydrophilic and hydrophobic materials. METHODS: Emulsions of oleophilic active ingredients and polyprotein microspheres are an important step to overcome insolubility issues. RESULTS: Polyprotein microspheres offer a versatile modifiable morphology, thermal responsivity, and size variation, which allows for the protection and release of assembled biomaterials. In addition, nanospheres present promising cell phagocytosis outcomes in vivo. CONCLUSION: In this research, a reproducible multifunctional approach, to assemble nanospheres in one step, using a technique termed "automatic nanoscalar interfacial alternation in emulsion" (ANIAE) was developed, incorporating a thermally controlled release mechanism for the assembled target active ingredients. These results demonstrate a viable, universal, multifunctional principal for the pharmaceutical industry.

Novel approach for real-time monitoring of carrier-based DPIs delivery process via pulmonary route based on modular modified Sympatec HELOS.

An explicit illustration of pulmonary delivery processes (PDPs) was a prerequisite for the formulation design and optimization of carrier-based DPIs. However, the current evaluation approaches for DPIs could not provide precise investigation of each PDP separately, or the approaches merely used a simplified and idealized model. In the present study, a novel modular modified Sympatec HELOS (MMSH) was developed to fully investigate the mechanism of each PDP separately in real-time. An inhaler device, artificial throat and pre-separator were separately integrated with a Sympatec HELOS. The dispersion and fluidization, transportation, detachment and deposition processes of pulmonary delivery for model DPIs were explored under different flow rates. Moreover, time-sliced measurements were used to monitor the PDPs in real-time. The Next Generation Impactor (NGI) was applied to determine the aerosolization performance of the model DPIs. The release profiles of the drug particles, drug aggregations and carriers were obtained by MMSH in real-time. Each PDP of the DPIs was analyzed in detail. Moreover, a positive correlation was established between the total release amount of drug particles and the fine particle fraction (FPF) values (R 2 = 0.9898). The innovative MMSH was successfully developed and was capable of illustrating the PDPs and the mechanism of carrier-based DPIs, providing a theoretical basis for the design and optimization of carrier-based DPIs.

Calcitriol tablets with hybrid lipid-based solid dispersions with enhanced stability and content uniformity.

Calcitriol, as the biologically active form of vitamin D3, is essential for patients with renal osteopathy. The solubilization, stabilization, and content uniformity are key issues in its formulation development. In our previous study, the incomplete release of calcitriol was solved by using the hybrid lipid-based solid dispersion (SD) for calcitriol. However, good stability and content uniformity are still urgently needed. In this study, solid lipid with antioxidant properties and liquid lipid compatible with calcitriol were employed as hybrid lipid carrier (HLC) to establish a solid dispersion. Moreover, the content uniformity of tablets with hybrid lipid carrier based SDs (HLCTs) was further guaranteed due to the multi-dispersion of calcitriol in HLC, solidification, and blank granules. Additionally, the compression of the blank granules was adjusted by the water content. The mixing method of calcitriol-containing and blank granules was also optimized. The obtained HLCTs were evaluated for hardness, disintegration time, in vitro drug dissolution, content uniformity, and stability. Satisfactory HLCTs were developed successfully in this study with superior content uniformity and better stability than the commercial soft capsule (Rocaltrol®). It was proved to be a promising formulation for drugs with poor water-solubility, instability to oxygen and heat, and dose-related toxicity.

Smart phase transformation system based on lyotropic liquid crystalline@hard capsules for sustained release of hydrophilic and hydrophobic drugs.

Smart phase transformation systems@hard capsule (SPTS@hard capsule) based on lyotropic liquid crystalline (LLC) were developed for oral sustained release in this study. Doxycycline hydrochloride (DOXY) and meloxicam (MLX) were used as hydrophilic and hydrophobic model drug, respectively. Two systems were added with different additives, that is, gelucire 39/01, PEG 1000 and Tween 80 to adjust their melting point and release profiles. The phase transformation of these systems could be triggered by water as well as temperature. They could spontaneously transform into cubic phase or hexagonal phase when coming across with water, to achieve the 24 h sustained release profile. In addition, the obtained systems could switch between semisolid state and liquid state when temperature changed within room temperature and body temperature, which facilitated the phase transformation in gastrointestinal tract and during their encapsulation into hard capsules. LLC-based SPTS@hard capsule revealed potential for the industrialization of its oral administration on account of its drugs accommodation with different solubility, controllable release profile and simple preparation process.

A Systematic Safety Evaluation of Nanoporous Mannitol Material as a Dry-Powder Inhalation Carrier System.

For carrier-based dry-powder inhaler (DPI) formulations, the adhesion between carrier particles and active pharmaceutical ingredients (API) particles have a significant influence on the aerosolization performance of the API-carrier complexes and the desired detachment of the API for efficient pulmonary delivery. In our previous study, nanoporous mannitol material was successfully fabricated as carriers by a one-step nonorganic solvent spray drying method with the thermal degradation of ammonium carbonate. These carriers were shown to achieve excellent aerosolization performance. In addition, no residue of ammonium carbonate was detected on the powder surface. However, the safety of nanoporous mannitol carriers (Nano-PMCs) during pulmonary administration/delivery was still unknown because the lung is vulnerable to the inhaled particles. To address this question, the present study was conducted to construct a systematic safety evaluation for DPIs carriers to investigate the safety of Nano-PMCs in the whole inhalation, which would make up for the lack of detailed and standardized method in this field. In vitro safety evaluation was carried out using respiratory and pulmonary cytotoxicity tests, hemolysis assay, and ciliotoxicity test. In vivo safety evaluation was studied by measuring inflammatory indicators in the bronchoalveolar lavage fluid, assessing the pulmonary function and observing pulmonary pathological changes. Nano-PMCs showed satisfactory biocompatibility on respiratory tracts and lungs in vitro and in vivo. It was suggested that Nano-PMCs were safe for intrapulmonary delivery and potential as DPI carriers.

Moisture-Resistant Co-Spray-Dried Netilmicin with l-Leucine as Dry Powder Inhalation for the Treatment of Respiratory Infections.

Netilmicin (NTM) is one of the first-line drugs for lower respiratory tract infections (LRTI) therapy, but its nephrotoxicity and ototoxicity caused by intravenous injection restrict its clinical application. Dry powder inhalation (DPI) is a popular local drug delivery system that is introduced as a solution. Due to the nature of NTM hygroscopicity that hinders its direct use through DPI, in this study, L-leucine (LL) was added into NTM dry powder to reduce its moisture absorption rate and improve its aerosolization performance. NTM DPIs were prepared using spray-drying with different LL proportions. The particle size, density, morphology, crystallinity, water content, hygroscopicity, antibacterial activity, in vitro aerosolization performance, and stability of each formulation were characterized. NTM DPIs were suitable for inhalation and amorphous with a corrugated surface. The analysis indicated that the water content and hygroscopicity were decreased with the addition of LL, whilst the antibacterial activity of NTM was maintained. The optimal formulation ND2 (NTM:LL = 30:1) showed high fine particle fraction values (85.14 ± 8.97%), which was 2.78-fold those of ND0 (100% NTM). It was stable after storage at 40 ± 2 °C, 75 ± 5% relative humidity (RH). The additional LL in NTM DPI successfully reduced the hygroscopicity and improved the aerosolization performance. NTM DPIs were proved to be a feasible and desirable approach for the treatment of LRTI.

Low density, good flowability cyclodextrin-raffinose binary carrier for dry powder inhaler: anti-hygroscopicity and aerosolization performance enhancement.

BACKGROUND: The hygroscopicity of raffinose carrier for dry powder inhaler (DPI) was the main obstacle for its further application. Hygroscopicity-induced agglomeration would cause deterioration of aerosolization performance of raffinose, undermining the delivery efficiency. METHODS: Cyclodextrin-raffinose binary carriers (CRBCs) were produced by spray-drying so as to surmount the above issue. Physicochemical attributes and formation mechanism of CRBCs were explored in detail. The flow property of CRBCs was examined by FT4 Powder Rheometer. Hygroscopicity of CRBCs was elucidated by dynamic vapor sorption study. Aerosolization performance was evaluated by in vitro deposition profile and in vivo pharmacokinetic profile of CRBC based DPI formulations. RESULTS: The optimal formulation of CRBC (R4) was proven to possess anti-hygroscopicity and aerosolization performance enhancement properties. Concisely, the moisture uptake of R4 was c.a. 5% which was far lower than spray-dried raffinose (R0, c.a. 65%). R4 exhibited a high fine particle fraction value of 70.56 ± 0.61% and it was 3.75-fold against R0. The pulmonary and plasmatic bioavailability of R4 were significantly higher than R0 (p < 0.05). CONCLUSION: CRBC with anti-hygroscopicity and aerosolization performance enhancement properties was a promising approach for pulmonary drug delivery, which could provide new possibilities to the application of hygroscopic carriers for DPI.