Spherical poly (D, L-lactic-co-glycolic acid) microparticles (PLGA-MPs) have long been investigated in order to achieve sustained delivery of proteins/peptides. However, the formation mechanism and ...release characteristics of the specific shape MPs were still unknown. This study aimed to develop a novel-dimpled exenatide-loaded PLGA-MPs (Exe-PLGA-MPs) using an ultra-fine particle processing system (UPPS) and investigate the formation mechanism and release characteristics. Exe-PLGA-MPs were prepared by UPPS and optimized based on their initial burst within the first 24 h and drug release profiles. Physicochemical properties of Exe-PLGA-MPs, including morphology, particle size, and structural integrity of Exe extracted from Exe-PLGA-MPs, were evaluated. Furthermore, pharmacokinetic studies of the optimal formulation were conducted in Sprague-Dawley (SD) rats to establish
in vitro
-
in vivo
correlations (
IVIVC
) of drug release. Exe-PLGA-MPs with dimpled shapes and uniform particle sizes achieved a high encapsulation efficiency (EE%, 91.50 ± 2.65%) and sustained drug release for 2 months
in vitro
with reduced initial burst (20.42 ± 1.64%). Moreover, the pharmacokinetic studies revealed that effective drug concentration could be maintained for 3 weeks following a single injection of dimpled Exe-PLGA-MPs with high
IVIVC
. Dimpled PLGA-MPs prepared using the UPPS technique could thus have great potential for sustained delivery of macromolecular proteins/peptides.
Previous studies have shown that combining colistin (Col), a cationic polypeptide antibiotic, with ivacaftor (Iva), a cystic fibrosis (CF) drug, could achieve synergistic antibacterial effects ...against
Pseudomonas aeruginosa
. The purpose of this study was to develop dry powder inhaler (DPI) formulations for co-delivery of Col and Iva, aiming to treat CF and lung infection simultaneously. In order to improve solubility and dissolution for the water insoluble Iva, Iva was encapsulated into bovine serum albumin (BSA) nanoparticles (Iva-BSA-NPs). Inhalable composite microparticles of Iva-BSA-NPs were produced by spray-freeze-drying using water-soluble Col as the matrix material and L-leucine as an aerosol enhancer. The optimal formulation showed irregular-shaped morphology with fine particle fraction (FPF) values of 73.8 ± 5.2% for Col and 80.9 ± 4.1% for Iva. Correlations between “
D
×
ρ
tapped
” and FPF were established for both Iva and Col. The amorphous solubility of Iva is 66 times higher than the crystalline solubility in the buffer. Iva-BSA-NPs were amorphous and remained in the amorphous state after spray-freeze-drying as examined by powder X-ray diffraction.
In-vitro
dissolution profiles of the selected DPI formulation indicated that Col and Iva were almost completely released within 3 hours, which was substantially faster regarding Iva release than the jet milled physical mixture of the two drugs. In summary, this study developed a novel inhalable nano-composite microparticle using a synergistic water-soluble drug as the matrix material, which achieved reduced use of excipients for high-dose medications, improved dissolution rate for the water-insoluble drug and superior aerosol performance.
The ultra-fine particle processing system (UPPS) previously developed by our lab has been used to prepare various microparticulate formulations. Microspheres prepared by UPPS can achieve sustained ...release with a reduced initial burst compared to the microspheres prepared by the conventional water-in-oil-in-water (W/O/W) double emulsion technique. However, the in vitro drug release mechanism of the microspheres prepared by UPPS is still uninvestigated. This study aimed to investigate the mechanisms of bovine serum albumin (BSA) released from poly (
d
,
l
-lactic-co-glycolic acid) (PLGA) microspheres prepared by UPPS in comparison with microspheres prepared by the W/O/W double emulsion technique. The morphology, in vitro drug release, water uptake, and structural evolution of microspheres prepared by both techniques were evaluated. UPPS microspheres showed solid and compact internal structures without any pores or channels thereby exhibiting a reduced rate of water permeation in the release medium. In addition, the release of BSA in UPPS microspheres was mainly controlled by the erosion of the polymer matrix during the entire process, while BSA was released from W/O/W microspheres by both drug diffusion and matrix erosion. Moreover, the observed surface and internal structural evolution also confirmed their different release mechanisms. This work elaborates the release mechanism of PLGA microspheres prepared by UPPS and facilitates the design of microparticulate formulations.
Graphical abstract
Nanocarrier-assisted pulmonary drug delivery system has been widely employed for lung local disease treatment due to its enhanced drug lesion accumulation and reduced systematical side effects. ...However, the mucus barriers covered on the epithelia of trachea and bronchial tree construct a dense barrier for inhaled nanocarrier transport, which compromises the therapeutical effects. In this study, a lipid liquid crystalline nanoparticle NLP@Z with surface zwitterion material hexadecyl betaine (HB) modification and
N
-acetylcysteine (NAC) encapsulation was presented to exert the combination strategy of mucus-inert surface and mucus degradation. The HB modification endowed NLP@Z mucus-inert surface to inhibit the interaction between NLP@Z and mucins, and the encapsulated NAC could effectively degrade the mucins and further decrease the mucus viscosity. This combination strategy was proved to significantly promote the mucus penetration performance and enhance epithelial cell uptake. In addition, the proposed NLP@Z was equipped with desired nebulization property, which could be served as a potential pulmonary delivery nanoplatform. In summary, the proposed NLP@Z highlights the employment of the combination strategy for mucus penetration enhancement in pulmonary delivery, which may become a versatile platform for lung disease therapy.
Graphical Abstract
The poly (lactic‐co‐glycolic acid) nanoparticle (PLGA NP) has been widely used in the biomedical field. However, it is insensitive to degradation upon laser irradiation, resulting in a limited ...increase in drug release, which compromises the therapeutic efficacy. To actively promote drug release, the biphasic α‐tocopheryl succinate (TPGS) functionalized PLGA NPs (PTNPs) are developed by introducing TPGS into the aqueous and organic phase to generate pores in the PLGA core during preparation. Paclitaxel and indocyanine green are encapsulated in the PTNPs to realize chemo‐photothermal combined therapy, and PTNPs are delivered through dissolving microneedles (DMNs) for local treatment in melanoma. PTNPs show enhanced drug release and improved cytotoxicity due to their greater ability in inhibiting cell microtubule depolymerization. In vivo tumor suppression investigation and ki‐67 immunohistochemical staining of tumor tissue further show the superiority of PTNPs loaded DMNs against tumor growth, and photothermal therapy synergistically enhances the chemotherapeutic effect of PTNPs. Moreover, the living imaging of mice demonstrates that the drug is successfully retained in the tumor tissue to avoid it entering into the circulation and producing adverse effects. Therefore, the PTNPs loaded DMNs show a favorable prospect in the treatment of superficial tumor.
α‐Tocopheryl succinate (TPGS) biphasic functionalized poly (lactic‐co‐glycolic acid) nanoparticles (PTNPs) are developed to actively facilitate drug release by using TPGS as a pore‐forming agent. In addition, the integration of PTNPs and dissolving microneedles (DMNs) technique avoids frequent administration and off‐target side effects. Effective treatment in melanoma is achieved through a single local administration of PTNPs loaded DMNs with chemo‐photothermal combined therapy.
The Multistage face gears are the core component of the planetary gear train, which is symmetrically meshed by multiple single-stage face gear and multiple cylindrical gears. However, it is difficult ...to synchronize the contact between face gears and cylindrical gear due to the tooth
number differences. Thus, the interference problems between two stages and big stress concentration are obvious. The crown surface configuration technology and structure design were introduced to optimize the meshing condition. To improve the double crown design feasibility and meshing stabillity,
it is necessary to establish a reasonable multistage face gears pair simulation model to evaluate various influence factors on the contact condition and quasi-static characteristics of multistage face gears structure. The relevant scatter plots are fitted by comparing the contact results with
different crown quantities and friction coefficients to intuitively obtain the variation regularity of maximum deformation, maximum strain, maximum stress and maximum strain energy. The natural frequency and mode coefficient are also determined by modal analysis under these two conditions.
All the above mentioned studies verified the contact conjugate properties of double crown surface configuration were suitable. The results can provide a foundation for structure optimization and transmission reliability of multistage face gears.
A novel self-developed technique ultra-fine particle process system (UPPS) was employed to develop sustained-release metoprolol tartrate (MT) microspheres for oral administration. Ethyl cellulose ...(EC) was selected as matrix, and Eudragit RS 100 was induced to regulate the viscosity and release profile of the MT microspheres. Single factor tests and L9 (33) orthogonal test were performed to optimize formulation, and the in vitro drug release, particle size, bulk density, flowability, scanning electron microscope (SEM), differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD) were characterized for the MT microspheres. The optimal formulation used for making microspheres was a dispersion with 5% (w/v) EC and 2% (w/v) Eudragit RS 100 in 80% (v/v) ethanol solution, and the drug MT content was 20% based on solid weight in the dispersion. The MT microspheres obtained by UPPS were approximate spheroidal solid particles with particle size in the range of 80 to 120μm and bulk density of 0.134±0.003g/cm3. Compared with blank microspheres, the MT microspheres possessed more round structure with uneven surface and better flowability due to their different formation process. It was indicated that MT was in amorphous form in the obtained microspheres and had no interactions with excipient by the DSC and XRD. 24h sustained-release microspheres were successfully achieved by UPPS for water-soluble MT. In addition, the in vitro drug release behaviors of the MT microspheres were similar in different release medium, indicating they would not be affected by pH value variation in gastrointestinal tract. All the result proved that the UPPS is a novel and promising technique for preparing sustained-release microspheres, and may be suitable for industrial production due to its successive and controllable step in preparation.
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•A novel self-developed ultra-fine particle process system was employed to prepare microspheres for oral administration.•The obtained MT microspheres by UPPS possessed good flowability, which were fit for tableting or capsulation.•The obtained MT microspheres by UPPS possessed pH-independent and 24 h-sustained release profile.•The capability of UPPS was proved that preparing sustained-release microspheres in one simple and controllable step.
Meat quality traits in yak are influenced by molecular genetic regulation, and hormone-sensitive lipase (HSL) is a potential gene affecting these traits. HSL is responsible for breaking down ...triacylglycerol in adipose tissue and releasing free fatty acids. Therefore, we used the competitive allele-specific polymerase chain reaction (KASP) technique to detect HSL genotypes and analyzed the associations between these genotypes and meat quality traits in yak. The HSL gene mutation affected meat tenderness, decreasing the value of Warner Bratzler shear force (WBSF). The highest HSL expression was noted in the adipose tissue of yak. These results suggest that the HSL gene affects the quality characteristics of yak meat by influencing the fatty acid composition. Hormone-sensitive lipase (HSL) is involved in the breakdown of triacylglycerols in adipose tissue, which influences muscle tenderness and juiciness by affecting the intramuscular fat content (IMF). This study analyzed the association between different genotypes and haplotypes of the yak HSL gene and carcass and meat quality traits. We used hybridization pool sequencing to detect exon 2, exon 8, and intron 3 variants of the yak HSL gene and genotyped 525 Gannan yaks via KASP to analyze the effects of the HSL gene variants on the carcass and meat quality traits in yaks. According to the results, the HSL gene is highly expressed in yak adipose tissue. Three single nucleotide polymorphisms (SNPs) were identified, with 2 of them located in the coding region and one in the intron region. Variants in the 2 coding regions resulted in amino acid changes. The population had 3 genotypes of GG, AG, and AA, and individuals with the AA genotype had lower WBSF values (p < 0.05). The H3H3 haplotype combinations could improve meat tenderness by reducing the WBSF values and the cooking loss rate (CLR) (p < 0.05). H1H1 haplotype combinations were associated with the increased drip loss rate (DLR) (p < 0.05). The presence of the H1 haplotype was associated the increased CLR in yaks, while that of the H2 haplotype was associated with the decreased DLR in yaks (p < 0.05). These results demonstrated that the HSL gene may influence the meat quality traits in yaks by affecting the IMF content in muscle tissues. Consequently, the HSL gene can possibly be used as a biomarker for improving the meat quality traits in yaks in the future.
Dry powder inhalers (DPIs) have been proposed as an alternative administration route for protein and peptide drugs. However, DPI particles are easy to aggregate due to the strong interactions between ...the particles, leading to poor aerosolization performance. In this study, fragmented particles containing octreotide acetate (OA) were prepared by spray drying technique for dry powder inhalation, which were expected to decrease the particle-particle interaction by reducing the contact sites. Mannitol and ammonium carbonate were used as protein stabilizer and fragment-forming agent, respectively. The obtained fragmented particles presented larger particle size, lower density, better dispersibility, and well in vitro aerodynamic behavior (emitted dose > 97%, fine particle fraction ≈ 40%). The circular dichroism spectrum results indicated that OA maintained the stability throughout the spray drying process. The relative bioavailability of dry powder inhalation (DPI) compared with subcutaneous injection of commercial product was up to 88.0%, demonstrating the feasibility of DPI for OA delivery. These results confirmed that the proposed fragmented particles had great potential for pulmonary delivery of protein and peptide drugs in a painless, rapid, and convenient manner.
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