Exploration of surface tension measurement methods for pharmaceutical excipients.

Surface tension is a crucial functional indicator for various classes of pharmaceutical excipients, as highlighted in both the Pharmacopoeia of the People's Republic of China (ChP) < 9601 Guidelines for Functionality-related Characteristics of Pharmaceutical Excipients > and the United States Pharmacopoeia (USP) < 1059 Excipient Performance >. However, there are few systematic studies on surface tension measurement of pharmaceutical excipients, resulting in a lack of stable parameter support in practical applications. In this study, we aim to fill this gap by exploring three different methods for measuring surface tension. These methods were carefully developed taking into account the actual measurement process and statistical theory, thus ensuring their applicability and reliability. Through comparative analyses, we have identified the most suitable measurement methods for different classes of pharmaceutical excipients. In addition, this paper describes the surface adsorption behavior of various excipients. Therefore, this study provides valuable guidance for the determination of surface tension and the study of surface adsorption behavior, which lays the foundation for further comprehensive research in the field of surface tension of pharmaceutical excipients and the improvement of general pharmacopoeia specification.

Spatiotemporally sequential delivery of biomimetic liposomes potentiates glioma chemotherapy.

As one of the most challenging cancers, glioma still lacks efficient therapeutic treatment in clinics. The dilemmas of nanodrug-based therapies for glioma are due not only the limited permeability of the blood-brain barrier (BBB) but also the deficiency of targeting tumor lesions. Thus, spatiotemporally sequential delivery of therapeutics from BBB-crossing to glioma accumulation is considered a strategy to obtain better outcomes. Here, we developed a biomimetic chemotherapy nanodrug composed of the hybrid membrane envelope of U87 cell membranes and RAW264.7 cell membranes, and the core of paclitaxel (PTX)-loaded liposome (PTX@C-MMCL). In the research, PTX@C-MMCL showed superior ability to cross the BBB via RAW264.7 cell membranes and accurate targeting to the brain tumor lesions relying on the homotypic targeting capacity of U87 cell membranes. Furthermore, PTX@C-MMCL can maintain a prolonged circulation in vivo. Importantly, PTX@C-MMCL effectively inhibited the development of glioma. Conclusively, our biomimetic nanodrug holds great potential for brain tumor targeting therapy.

Redox-sensitive polyglutamic acid-platinum(IV) prodrug grafted nanoconjugates for efficient delivery of cisplatin into breast tumor.

Targeting cisplatin to the sites of action and decreasing its side effects are still major challenges. Here, we introduced a polyglutamic acid-platinum(IV) prodrug nanoconjugates (γ-PGA-CA-Pt(IV)) constructed by polyglutamic acid and modified platinum(IV) prodrug to reserve the anti-tumor efficacy of cisplatin with decreased side effects. We describe the synthesis, physico-chemical characterization, and redox- and pH-sensitive releasing behavior of the nanoconjugate. In vitro studies revealed that, when incubated with glutathione in advance, the γ-PGA-CA-Pt(IV) nanoconjugate induced significant apoptosis in human breast carcinoma MCF-7 cells. From in vivo antitumor efficacy evaluation, the γ-PGA-CA-Pt(IV) nanoconjugate obviously improved the survival rate of tumor-bearing mice with inhibition of the tumor growth compared with cisplatin. Meanwhile, the nanoconjugates showed remarkable improved safety profile than the free cisplatin.

A Raman imaging-based technique to assess HPMC substituent contents and their effects on the drug release of commercial extended-release tablets.

In this study, we tried to assess the substitute contents of HPMC used in commercial extended-release tablets directly by an innovative Raman imaging-based analysis technique and find their effects on the in vitro performance of these pharmaceuticals. Twenty-seven batches of metformin hydrochloride extended-release tablets from various sources were collected in the Chinese mainland market. While Raman imaging was used to qualitatively analyze the composition of the tablets, the MeO and HPO contents of HPMC were quantitatively assessed by a newly proposed calculation method based on the Raman intensity of corresponding characteristic band. Additionally, the dissolution test was performed to evaluate the relationship between HPMC substitution pattern and in vitro behavior. In sum, our findings indicate that the drug release rate can be downregulated by increasing the MeO content of HPMC, while the high HPO content would largely eliminate the variation of drug release profiles among batches.

Fumaryl diketopiperazine based effervescent microparticles to escape macrophage phagocytosis for enhanced treatment of pneumonia via pulmonary delivery.

The treatment of pulmonary infections with antibiotics administered via pulmonary delivery provides for higher local therapeutic efficacy rather than through systemic administration. Pneumonia is globally considered a major cause of death due to a lack of proper medication. The treatment of pneumonia with inhalable antibiotics (such as azithromycin (AZM)) can provide a maximum pulmonary therapeutic effect without significant systemic side effects. Compared to non-effervescent microparticles, effervescent microparticles can provide an active driving force to release loaded antibiotics for subsequent distribution deep into the lung by virtue of its smaller size. In this study, N-fumaroylated diketopiperazine (FDKP) was used as a carrier to prepare effervescent inhalable microparticles loaded with AZM (AZM@FDKP-E-MPs). This effervescent dry powder was characterized for both in vitro and in vivo deposition in the lung and the results obtained showed significant improvement in lung deposition and anti-bacterial efficiency, suggesting a strong potential application for pneumonia treatment.

Cisplatin-stitched α-poly(glutamatic acid) nanoconjugate for enhanced safety and effective tumor inhibition.

Conjugation of cisplatin to macromolecular carriers has been extensively studied for reducing systemic side effects. Here, a cisplatin-stitched α-poly(glutamatic acid) nanoconjugate with reduced adverse reactions and effective anti-tumor efficacy was synthesized via ionic interaction between platinum ion of cisplatin with carboxylic groups of α-poly(glutamatic acid). The nanoconjugate exhibited good water solubility, suitable size and polydispersity, almost spherical morphologies, and a sustained release profile without burst release. In vitro cytotoxicity and cell apoptosis assays performed in MCF-7 cells showed significantly decreased cytotoxicity of nanoconjugate compared with free cisplatin, and larger ratio of early apoptosis than late apoptosis. Quantitative cellular uptake assay also supported that conjugation of cisplatin to α-poly(glutamatic acid) reduced its cytotoxicity. Further studies revealed that the unique space structure of nanoconjugate acted as a shield for cisplatin against GSH detoxification under physiological conditions. In vivo studies regarding maximum tolerated dose, hematological parameters evaluation and histopathology assay demonstrated the superior safety of nanoconjugates. Furthermore, the nanoconjugates also achieved comparable antitumor efficacy with no apparent weight loss and death at a high equivalent cisplatin dose of 25 mg/kg. Moreover, the survival rate of mice treated with nanoconjugate was greatly larger than that of free cisplatin. These findings suggest that the cisplatin-stitched α-poly(glutamatic acid) nanoconjugate may hold great potential in clinical application for cancer therapy.

Efficient delivery of paclitaxel into ASGPR over-expressed cancer cells using reversibly stabilized multifunctional pullulan nanoparticles.

Core-crosslinked pullulan nanoparticles (Pull-LA-CLNPs) were synthesized by the reduction-sensitive strategy for paclitaxel (PTX) delivery. Pull-LA-CLNPs showed high stability against extensive dilution, high salt concentration and organic solvent. In vitro drug release study showed that PTX release from Pull-LA-NPs at pH 7.4 and 5.4 was significantly influenced by addition of DTT. In cytotoxicity assay, PTX loaded Pull-LA-CLNPs showed a low IC50 at 0.51µg/mL. Asialoglycoprotein receptor (ASGPR) competitive inhibition and intracellular distribution studies performed by flow cytometer, fluorescence microscope and confocal laser scanning microscopy (CLSM) showed that Pull-LA-NPs could be efficiently taken up by the cells via ASGPR-mediated endocytosis and mainly distributed in cytoplasm. From in vivo pharmacokinetics study, Pull-LA-CLNPs displayed the longest systemic retention time and slowest plasma elimination rate in comparison with Taxol and Pull-LA-NCLNPs. In conclusion, Pull-LA-CLNPs is a promisingly safe, biodegradable and cell-specific nano-carrier to deliver lipophilic anticancer drugs.

Risk assessment of supply chain for pharmaceutical excipients with AHP-fuzzy comprehensive evaluation.

As the essential components in formulations, pharmaceutical excipients directly affect the safety, efficacy, and stability of drugs. Recently, safety incidents of pharmaceutical excipients posing seriously threats to the patients highlight the necessity of controlling the potential risks. Hence, it is indispensable for the industry to establish an effective risk assessment system of supply chain. In this study, an AHP-fuzzy comprehensive evaluation model was developed based on the analytic hierarchy process and fuzzy mathematical theory, which quantitatively assessed the risks of supply chain. Taking polysorbate 80 as the example for model analysis, it was concluded that polysorbate 80 for injection use is a high-risk ingredient in the supply chain compared to that for oral use to achieve safety application in clinic, thus measures should be taken to control and minimize those risks.

Risk assessment of supply chain for pharmaceutical excipients with AHP-fuzzy comprehensive evaluation.

As the essential components in formulations, pharmaceutical excipients directly affect the safety, efficacy, and stability of drugs. Recently, safety incidents of pharmaceutical excipients posing seriously threats to the patients highlight the necessity of controlling the potential risks. Hence, it is indispensable for the industry to establish an effective risk assessment system of supply chain. In this study, an AHP-fuzzy comprehensive evaluation model was developed based on the analytic hierarchy process and fuzzy mathematical theory, which quantitatively assessed the risks of supply chain. Taking polysorbate 80 as the example for model analysis, it was concluded that polysorbate 80 for injection use is a high-risk ingredient in the supply chain compared to that for oral use to achieve safety application in clinic, thus measures should be taken to control and minimize those risks.

Antitumor activity of TNF-α after intratumoral injection using an in situ thermosensitive hydrogel.

Local drug delivery strategies based on nanoparticles, gels, polymeric films, rods and wafers are increasingly used in cancer chemotherapy in order to enhance therapeutic effect and reduce systemic toxicity. Herein, a biodegradable and biocompatible in situ thermosensitive hydrogel was designed and employed to deliver tumor necrosis factor-α (TNF-α) locally by intratumoral injection. The triblock copolymer was synthesized by ring-opening polymerization (ROP) of ß-butyrolactone (ß-BL) and lactide (LA) in bulk using polyethylene glycol (PEG) as an initiator and Sn(Oct)2 as the catalyst, the polymer was characterized by NMR, gel permeation chromatography and differential scanning calorimetry. Blood and tumor pharmacokinetics and in vivo antitumor activity of TNF-α after intratumoral administration in hydrogel or solution with the same dose were evaluated on S180 tumor-bearing mice. Compared with TNF-α solution, TNF-α hydrogel exhibited a longer T1/2 (4-fold) and higher AUCtumor (19-fold), but Cmax was lower (0.5-fold), which means that the hydrogel formulation improved the efficacy with a lower systhemic exposure than the solution formation. In addition, TNF-α hydrogel improved the antitumor activity and survival due to lower systemic exposure than the solution. These results demonstrate that the in situ thermosensitive hydrogel-based local delivery system by intratumoral injection is well suited for the administration of TNF-α.

Preparation and in vitro characterization of thermosensitive and mucoadhesive hydrogels for nasal delivery of phenylephrine hydrochloride.

The aim of the present work was to develop a nasal delivery system of phenylephrine hydrochloride (PE) in spray form to make prolonged remedy of nasal congestion. The formulations contain the thermosensitive hydrogel, i.e., Poloxamer 407 (P407) and Poloxamer 188 (P188) mixtures, and mucoadhesives, i.e., ε-polylysine (ε-PL) and low molecular weight sodium hyaluronate (MW 11,000Da). The in vitro characterizations of formulations including rheology studies, texture profiles and in vitro mucoadhesion potential were investigated after gelation temperatures measurements. The results showed that the concentration of P407 or P188 had significant influence on gelation temperature and texture profiles. The addition of mucoadhesives, though lowered the gel strength of formulations, increased interaction with mucin. After screening, two formulations (i.e., 1.0% PE/0.5% ε-PL/17% P407/0.5% P188 or Formulation A; and 1.0% PE/0.5% HA/17% P407/0.8% P188 or Formulation B) presenting suitable gelation temperatures (∼32°C) were used for further studies on in vitro release behaviors and mucosa ciliotoxicity. Both formulations showed sustained release of PE for up to 8h and similar toxicity to saline, the negative control. Thus, the thermosensitive and mucoadhesive PE-containing hydrogels are promising to achieve prolonged decongestion in nasal cavity.

Novel designed polyoxyethylene nonionic surfactant with improved safety and efficiency for anticancer drug delivery.

In order to limit the adverse reactions caused by polysorbate 80 in Taxotere(®), a widely used formulation of docetaxel, a safe and effective nanocarrier for this drug has been developed based on micelles formed by a new class of well-defined polyoxyethylene sorbitol oleate (PSO) with sorbitol as the matrix in aqueous solution. The physicochemical properties of the amphiphilic surfactant and the resulting micelles can be easily fine-tuned by the homogeneous sorbitol matrix and pure oleic acid. Composition, critical micelle concentration, and entrapment efficiency were investigated by ultraviolet visible spectroscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorospectrophotometry, and high-performance liquid chromatography. In vitro and in vivo evaluation revealed that PSO had exceptionally low hemolysis and histamine release rates compared with commercial polysorbate 80. Moreover, the tumor targeting delivery of PSO was investigated by in vivo imaging in S180 tumor-bearing mice. The results suggest that this novel delivery system, PSO, provides an acceptable alternative to polysorbate 80 for delivery of docetaxel. Further, due to the hypoallergenic nature of PSO, the mechanism of pseudoallergy caused by the polyoxyethylene nonionic surfactant was investigated. Based on in vitro cell analysis, it was assumed that the initial contact of polyoxyethylene nonionic surfactant with mast cells provoked pseudoallergy via polyamine receptor-mediated endocytosis.

Synthesis, characterization, biodegradability and biocompatibility of a temperature-sensitive PBLA-PEG-PBLA hydrogel as protein delivery system with low critical gelation concentration.

Temperature-sensitive hydrogels were designed using a series of A-B-A triblock copolymers consisting of poly (ethylene glycol) (PEG) with different molecular weights as the hydrophilic block B and poly (ß-butyrolactone-co-lactic acid)(PBLA) with varying block lengths and composition as the hydrophobic block A. The triblock copolymers were synthesized by ring-opening polymerization (ROP) of ß-BL and LA in bulk using PEG as an initiator and Sn(Oct)2 as the catalyst. Their chemical structure and molecular characteristics were determined by NMR, GPC and DSC, and the relationship between structure and phase behaviors in aqueous solutions was investigated as well. It was found that the phase behaviors in aqueous solutions including critical micelle concentration (CMC), sol-gel-sedimentation phase transition temperature, gel window width and critical gelation concentration (CGC) are largely dependent on the molecular weight and block length ratio of PEG/PBLA. Most importantly, they show a very low CGC ranging from 4 to 8 wt% because of the introduction of ß-BL. Furthermore, the biodegradability and biocompatibility of the hydrogels were evaluated. Finally, lysozyme as a model protein was used to evaluate the ability to deliver protein drugs in a sustained release manner and biologically active form. All results demonstrated that the temperature-sensitive in situ forming hydrogel has a promising potential as sustained delivery system for protein drugs.

A poly(γ, L-glutamic acid)-citric acid based nanoconjugate for cisplatin delivery.

A cisplatin-loaded nanoconjugate, poly(γ, L-glutamic acid)-citric acid-cisplatin [γ-PGA-CA-CDDP], as a tumor-targeted drug delivery system with sustained release capacity was successfully synthesized and characterized, and its antitumor activity was evaluated. The particle size (107 ± 6.3 nm) and average molecular weight (66 kDa) were determined by dynamic light scattering (DLS) and gel permeation chromatography (GPC), respectively. The nanoconjugate delivery system released platinum in a sustained manner in PBS at 37 °C with an initial burst release during the first 8 h and 50% cumulative release within 48 h. Both in-vitro and in-vivo studies showed that the toxicity of γ-PGA-CA-CDDP nanoconjugate significantly decreased by comparison to that of unconjugated CDDP. The maximum tolerated dose (MTD) of γ-PGA-CA-CDDP nanoconjugate was about 38 mg/kg versus 8 mg/kg for CDDP. No apathy or acute adverse reactions were observed in γ-PGA-CA-CDDP nanoconjugate groups while mice expressed apathy at all dose levels with CDDP treatment. In ICR mice, the area under the curve and total body clearance values for γ-PGA-CA-CDDP nanoconjugate were 9-fold and one-twentieth of the values for CDDP, respectively. With the aid of near-infrared fluorescence (NIRF) imaging system, it was demonstrated that γ-PGA-CA-CDDP nanoconjugate gradually accumulated at the tumor site within 15 min postinjection and exhibited prolonged retention for more than 8 h. In H22-implanted mice, γ-PGA-CA-CDDP showed a significantly higher antitumor activity versus CDDP. These results reveal that γ-PGA-CA-CDDP nanoconjugate with improved stability, reduced toxicity and prolonged in-vivo retention time holds great potential in terms of clinical application to cancer therapy.