Study on the Nasal Drug Delivery System of NMD Liposomes In Situ Thermosensitive Gel.

Nimodipine (NMD) is a 1,4-dihydropyridine calcium antagonist that is effective in the prevention and treatment of cerebral arterial vasospasm and cerebral ischemic injury caused by subarachnoid hemorrhage. Since the drug itself is highly insoluble in water and has low oral bioavailability, while injectable formulations may cause pain and inflammation, the blood-brain barrier (BBB) prevents the effective delivery of therapeutic agents to the brain tissue. Therefore, in the present study, NMD liposomes were prepared by ethanol injection and innovatively lyophilised and loaded into temperature-sensitive in situ gels for intranasal administration as sprays to deliver drugs to brain tissues bypassing the blood-brain barrier. The optimal gel formulation was obtained by screening in which liposomes were divided into lecithin, cholesterol, and NMD in the ratio of 40:10: 1; Pluronic P407, Pluronic P188, Tween 80, polyvinyl ketone and ethyl nipagin in the ratio of (180:20:3:1:1); Pluronic P407, Pluronic P188, Tween 80, polyvinyl ketone, and ethyl nipagin in the ratio of (180:20:3:1:1). The prepared flow gel can form a solidified gel after a temperature of 31.07-32.07°C and a time of 58.51-59.89 s. Meanwhile, the NMD liposome gel formulation achieved sustained release over 56 h. The pharmacokinetic results of the developed NMD liposomal temperature-sensitive in situ gel and NMD temperature-sensitive in situ gel showed that liposomal nasal mucosal in situ gel is a more effective brain-targeted drug delivery system for NMD.

In situ gelling hydrogel loaded with berberine liposome for the treatment of biofilm-infected wounds.

Background: In recent years, the impact of bacterial biofilms on traumatic wounds and the means to combat them have become a major research topic in the field of medicine. The eradication of biofilms formed by bacterial infections in wounds has always been a huge challenge. Herein, we developed a hydrogel with the active ingredient berberine hydrochloride liposomes to disrupt the biofilm and thereby accelerate the healing of infected wounds in mice. Methods: We determined the ability of berberine hydrochloride liposomes to eradicate the biofilm by means of studies such as crystalline violet staining, measuring the inhibition circle, and dilution coating plate method. Encouraged by the in vitro efficacy, we chose to coat the berberine hydrochloride liposomes on the Poloxamer range of in-situ thermosensitive hydrogels to allow fuller contact with the wound surface and sustained efficacy. Eventually, relevant pathological and immunological analyses were carried out on wound tissue from mice treated for 14 days. Results: The final results show that the number of wound tissue biofilms decreases abruptly after treatment and that the various inflammatory factors in them are significantly reduced within a short period. In the meantime, the number of collagen fibers in the treated wound tissue, as well as the proteins involved in healing in the wound tissue, showed significant differences compared to the model group. Conclusion: From the results, we found that berberine liposome gel can accelerate wound healing in Staphylococcus aureus infections by inhibiting the inflammatory response and promoting re-epithelialization as well as vascular regeneration. Our work exemplifies the efficacy of liposomal isolation of toxins. This innovative antimicrobial strategy opens up new perspectives for tackling drug resistance and fighting wound infections.

Preparation of Cod Skin Collagen Peptides/Chitosan-Based Temperature-Sensitive Gel and Its Anti-Photoaging Effect in Skin.

Background: Photoaging decreases quality of life and increases the risk of skin cancer, underscoring the urgent need to explore natural, high-efficacy, anti-skin photoaging (SP) active substances. Methods: In this study, a gel (CS/CSCPs/ß-GP gel) was prepared using chitosan (CS) and sodium ß-glycerophosphate (ß-GP) through crosslinking with small molecular CSCPs as the carried drug. We evaluated its structural characteristics and properties. The effect of CS/CSCPs/ß-GP gel on the degree of ultraviolet (UV)-induced skin aging of mice was investigated through comparative analysis of skin damage, the integrity of collagen tissues and elastic fibers, levels of reactive oxygen species (ROS) and key inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß, IL-6, and IL-10), and tissue expression of matrix metalloproteinase-3 (MMP-3) after repeated UV irradiation in a nude mice SP model. Results: The results showed that CS/CSCPs/ß-GP gel was successfully prepared and had the desired characteristics. Compared with CSCPs alone, the CS/CSCPs/ß-GP gel more evidently improved typical photoaging characteristics on mouse dorsal skin. It also increased the moisture content, causing the skin to become glossy and elastic. Pathological skin analysis revealed that this peptide-carrying gel can effectively inhibit epidermal thickening, reduce tissue inflammatory infiltration, suppress collagen fiber degradation, increase the collagen content, alleviate structural elastic fiber damage, and significantly inhibit abnormal MMP-3 expression. In addition, biochemical analysis showed that the CS/CSCPs/ß-GP gel can effectively inhibit the elevated expressions of ROS and key proinflammatory factors (TNF-α, IL-1ß, IL-6) in photoaging skin tissues and promote expression of the anti-inflammatory factor IL-10. Conclusion: SP can cause many clinical skin diseases, such as solar freckle-like nevus, solar keratosis, cutaneous melanoma, and squamous cell carcinoma. CSCPs are a high-efficacy anti-SP natural active substance and CS/CSCPs/ß-GP gel can synergistically enhance the CSCPs' anti-SP effect. The mechanism is likely related to the inhibited activation of ROS/nuclear transcription factor-κB signaling and the expression of downstream inflammatory factors.

Effect of Xileisan temperature-sensitive gels on endothelial nitric oxide synthase, vascular endothelial growth factor A and tumor necrosis factor-α expression in rats with bleeding internal hemorrhoids / 预防医学

Objective@#To investigate the effect of Xileisan temperature-sensitive gels on endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor A (VEGF-A) and tumor necrosis factor-α (TNF-α) expression in rats with bleeding internal hemorrhoids, so as to provide insights into the illustration of the pathogenesis of internal hemorrhoid hemorrhage. @*Methods@#Thirty six-week-old SPF-graded rats of the SD strain were randomly divided into the normal group, model group and Xileisan temperature-sensitive gel group, of 10 rats in each group (half male and half female). Cotton balls were soaked with 0.16 mL of croton oil mixture and then inserted into the anus of rats in the model group and Xileisan temperature-sensitive gel group for 10 s. After 6 h when the rectal mucosa tissues presented remarkable swelling, the perianal mucosa was rubbed repeatedly with a rough glass rod until the glass rod was bloody. Following successful modeling, rats in the Xileisan temperature-sensitive gel group was given rectal administration of Xileisan temperature-sensitive gel at a dose of 0.5 mL/d, while animals in the normal group and model group were given rectal administration of the blank gel at the same dose. Following administration for 7 successive days, rats were sacrificed, and the hemorrhoids tissues were collected for pathological examinations. The eNOS, VEGF-A and TNF-α expression was determined using immunohistochemistry and compared among groups.@*Results@#Compared with the normal group, the rat hemorrhoids mucosa showed inflammatory changes in the model group, with submucosal congestion and edema, blood vessel congestion and dilation, and visible new blood vessels, and remarkable improvements were seen in the hemorrhoid mucosal inflammation in the Xileisan temperature-sensitive gel group. There were significant differences in the integrated option density (IOD) of eNOS and VEGF-A expression in rat hemorrhoids tissues among the three groups (P<0.05), and no gender-specific differences were seen (P>0.05). The IOD values of eNOS (45.84±13.66) and VEGF-A expression (45.89±9.06) were higher in rat hemorrhoids tissues in the model group than in the normal group (23.11±5.64 and 27.91±11.65) and the Xileisan temperature-sensitive gel group (27.41±8.89 and 33.44±6.20) (P<0.05), while no significant differences were detected in the IOD of TNF-α expression in rat hemorrhoids tissues among the three groups (P>0.05).@*Conclusion@#Xileisan temperature-sensitive gel may alleviate inflammation and internal hemorrhoids hemorrhage through inhibiting eNOS and VEGF-A expression in rat hemorrhoids tissues.

Metal-organic framework IRMOFs coated with a temperature-sensitive gel delivering norcantharidin to treat liver cancer.

BACKGROUND: Norcantharidin (NCTD) is suitable for the treatment of primary liver cancer, especially early and middle primary liver cancer. This compound can reduce tumors and improve immune function. However, the side effects of NCTD have limited its application. There is a marked need to reduce the side effects and increase the efficacy of NCTD. AIM: To develop a nanomaterial carrier, NCTD-loaded metal-organic framework IRMOF-3 coated with a temperature-sensitive gel (NCTD-IRMOF-3-Gel), aiming to improve the anticancer activity of NCTD and reduce the drug dose. METHODS: NCTD-IRMOF-3-Gel was obtained by a coordination reaction. The apparent characteristics and in vitro release of NCTD-IRMOF-3-Gel were investigated. Cell cytotoxicity assays, flow cytometry, and apoptosis experiments in mouse hepatoma (Hepa1-6) cells were used to determine the anti-liver cancer activity of NCTD-IRMOF-3-Gel in in vitro models. RESULTS: The particle size of NCTD-IRMOF-3-Gel was 50-100 nm, and the particle size distribution was uniform. The release curve showed that NCTD-IRMOF-3-Gel had an obvious sustained-release effect. The cytotoxicity assays showed that the free drug NCTD and NCTD-IRMOF-3-Gel treatments markedly inhibited Hepa1-6 cell proliferation, and the inhibition rate increased with increasing drug concentration. By flow cytometry, NCTD-IRMOF-3-Gel was observed to block the Hepa1-6 cell cycle in the S and G2/M phases, and the thermosensitive gel nanoparticles may inhibit cell proliferation by inducing cell cycle arrest. Apoptosis experiments showed that NCTD-IRMOF-3-Gel induced the apoptosis of Hepa1-6 cells. CONCLUSION: Our results indicated that the NCTD-IRMOF-3-Gel may be beneficial for liver cancer disease treatment.

Intranasal tetrandrine temperature-sensitive gel for treatment of post-traumatic stress disorder / 药学学报

The traditional systemic treatment of post-traumatic stress disorder (PTSD) requires a long time period for an effect and has obvious side effects. In this study, tetrandrine temperature-sensitive gel (TTG) was prepared for treatment of PTSD in mice by nasal administration. TTG was prepared with poloxamer as matrix, the gelation temperature was suitable (<32 ℃) and the gelation time was short (1.32 min). Rheology experiments demonstrated that TTG has temperature sensitivity. In vivo imaging system of small animals proved that TTG nasal cavity retention time was so long. The cilia toxic test of toad showed that the formulation was safe. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. The mice were randomly assigned into healthy group, model group and TTG group. The PTSD model of mice was established by single prolonged stress (SPS) and foot-shock method to generate anxiety and fear behavior. On the day 0 of TTG administration, SPS model mice were evaluated by the elevated plus maze (EPM). Percentages of open arm entries number (OE), latency of open arm entries (OL) and the residence time of open arm entries (OT) all indicated that the SPS model was successfully established. On the 7th day of TTG administration, TTG increased the OE and OT, decreased the OL of SPS mice. The feard behavior of mice in the foot-shock model was tested using conditioned fear box, 7 days of TTG treatment can reduce the freezing time of the mice obviously. The pathological changes of hippocampus, prefrontal cortex and amygdala were observed by H&E histological sections and c-fos immunohistochemical expression. The main influenced areas of PTSD were revealed to be the CA1 of hippocampus, prefrontal cortex and amygdala. All of the above indicated that TTG is a convenient, safe and effective drug for PTSD treatment, and will provide a new choice for clinical management of PTSD.

Chitosan temperature-sensitive gel loaded with drug microspheres has excellent effectiveness, biocompatibility and safety as an ophthalmic drug delivery system.

In the present study, a temperature-sensitive gel composed of chitosan, carboxymethyl chitosan and glycerophosphate was prepared and loaded with chitosan microspheres encapsulating levofloxacin. The bioavailability of levofloxacin and the safety of this novel opthalmic drug delivery formulation were evaluated. Levofloxacin chitosan microspheres were prepared using the ionic gelation method, and the particle size and entrapment rate were determined. The morphology of the microspheres was observed by scanning electron microscopy. The pH and zeta potential were measured. The in vitro release of levofloxacin by the chitosan temperature-sensitive gel loaded with drug microspheres was determined using spectrophotometry. The eye retention time of the chitosan temperature-sensitive gel was calculated using a fluorescein sodium test. To assess the bioavailability and safety of the chitosan temperature-sensitive gel, a cell compatibility test, a cytotoxicity test and skin irritation test were performed. The entrapment rate of levofloxacin in the chitosan microspheres was determined to be 26.5%. The levofloxacin chitosan microspheres that were formed by chitosan and sodium tripolyphosphate were identified to be suitable for use in an ophthalmic particle dispersion system based on their physical and chemical properties. The pH of the levofloxacin chitosan microsphere suspension was 5.87±0.04, the average particle diameter was 2,452±342 nm, the polydispersity index was 0.168±0.028 and the ζ potential was 28.62±1.7 mV. The chitosan temperature-sensitive gel carrying microspheres loaded with drug prevented drug burst release at the initial stage and facilitated the slow release of the drug later on. Furthermore, this delivery system markedly prolonged the contact duration of levofloxacin with the eye. The chitosan temperature-sensitive hydrogel was safe and provided a good bioavailability of the drug. The results revealed that the chitosan temperature-sensitive gel had a cytotoxicity of grade 0, and no erythematous response was observed during the entire course of the skin irritation test. The present study provided a basis for the future development of the chitosan-based temperature-sensitive hydrogel in ophthalmic drug delivery.

Study on the Effect of 1-Butanol Soluble Lignin on Temperature-Sensitive Gel.

A protocol for the fractionation of lignin with 1-butanol as solvent has been proposed in order to improve the utilization of industry alkali lignin. 1-butanol soluble lignin (BSL) was used as a building block for temperature-sensitive hydrogel with N-isopropylacrylamide (NIPAAm) through graft polymerization. The result shows that 1-butanol fractionation is an effective method to improve the molecular weight homogeneity of lignin (PDI, 2.5 to 1.83) and increase the hydroxyl group content (0.585⁻1.793 mmol/g). The incorporation of BSL into the temperature-sensitive hydrogel can enhance the thermal stability and increase the hydrophobicity of the gel, which leads to a decrease in lower critical solution temperature (LCST). In addition, the compression strength, swelling ratio, and pore size of the gel can be adjusted by the dosage of lignin. This stimuli-responsive gel, with an LCST around 32 °C, is expected to be applied in the agricultural field as a pesticide carrier by stimulating release and absorption properties based on the change in natural environmental temperature.

Preparation and preliminary evaluation of chitosan composite KGF-2 mutant thermal sensitive dressing / 军事医学

Objective To develop chitosan composite keratinocyte growth factor-2 mutant(KGF-2M)temperature-sen-sitive dressing and evaluate its physicochemical properties and dynamic release rule were used.Methods Chitosan, chi-tosan quaternary ammonium salt,β-glycerophosphate and other adjuvant materials to configure different formulations which were compounded with KGF-2M in order to develop temperature-sensitive dressing.Gelling time, temperature,the release rate of KGF-2M and other indicators were measured to analyze the physical and chemical properties of the temperature -sen-sitive dressing.Results Chitosan-KGF-2M composite dressing with temperature-sensitive properties was obtained by opti-mizing the formulation components of chitosan and related adjuvant materials.When the liquid dressing was above 35℃,it could be converted from liquid to solid gelatin within 10 minutes.The compound KGF-2M released from the gel was more than 98%at 4 h,and its bioactivity remained stable.Conclusion The thermo-sensitive gel has the characteristics of good conformability,moisturizing(moisture),isolation,wound healing,and a controlled release effect,which has great potential in wartime for wound repair.

Preparation and Quality Analysis of Osthole Microcapsules-Temperature-sensitive Gel / 中国药学杂志

OBJECTIVE: To optimize the preparation process of osthole microcapsules-temperature-sensitive gel and set up its quality standard. METHODS: Using gelling temperature as the indicator, P407, P188 and the concentration of propylene glycol were investigated by single factor test, and orthogonal experiment was conducted to optimize the preparation process of osthole microcapsules-temperature-sensitive gel. Osthole content was determined by HPLC. The quality standard of osthole microcapsules-temperature-sensitive gel was established. RESULTS: The optimal formulation of osthole microcapsules-temperature-sensitive gel was as followsP407-P188-propylene glycol=18%∶1%∶15%. Osthole contentin the osthole microcapsules-temperature-sensitive gel should not be less than 31.77 μg·mL-1, and the gelling temperature should be 36-37℃. CONCLUSION: Osthole microcapsules-temperature-sensitive gel prepared in this study has reasonable composition, simple preparation process, and stable quality standards, indicating a hopeful application prospect.

Formula Screening and in vitro Drug Release of Tegafur Thermo-sensitive Gel for Intratumor Injection / 中国药师

Objective:To screen the best formula of tegafur temperature-sensitive gel for intratumor injection and investigate the in vitro drug release behavior. Methods:The drug dose was determined by cytotoxicity experiment. The thermo-sensitive gel was prepared with PLGA-PEG-PLGA and HPMC as the matrix. With the in vitro release as the index, the effects of PLGA-PEG-PLGA and HPMC at different concentrations on gel were investigated. The gelation temperature, viscosity and pH were detected. Results:The best formula was as follows:25% PLGA-PEG-PLGA, 1% HPMC, and tegafur dose of 1 mg·ml-1 . The average gelation temperature was 36. 7℃, the average viscosity was 7550 mPa·s, and the average pH was 7. 2. Conclusion:Tegafur thermo-sensitive gel for intratumor in-jection shows temperature sensitivity and obvious sustained-release property, which provides experimental basis for the further clinical research.