Transdermal administration of ibuprofen-loaded hexagonal liquid crystal gel for enhancement of drug concentration in the uterus: in vitro and in vivo evaluation.

Primary dysmenorrhea is a common disease in women, and oral administration of Ibuprofen (IBU) is associated with first-pass effects and gastrointestinal irritation. Here, we developed ibuprofen-loaded hexagonal liquid crystal (IBU HLC) gel for transdermal administration. In this study, the structure of prepared IBU HLC was characterized using polarizing microscopey (PLM) and small angle X ray diffraction (SAXS). In vitro drug release behavior and percutaneous penetration were investigated, and drug transdermal behavior was observed by confocal laser scanning microscope (CLSM). Finally, the pharmacokinetic profile and tissue distribution were investigated after transdermal administration. The PLM and SAXS results showed that the inner structure of IBU HLC was hexagonal phase. Moreover, in vitro release, skin permeation and CLSM demonstrated that IBU HLC had an excellent sustained-release effect, and a good transdermal penetration effect accompanied by the combination of multiple percutaneous routes. Pharmacokinetic studies indicated that IBU entered the blood circulation through abdominal transdermal administration in small amounts, mainly entering the uterus, and had a certain targeting ability. In conclusion, the IBU HLC gel would be a promising sustained-release preparation for transdermal administration to relieve dysmenorrhea with a significant drug concentration in the uterus.

Self-Emulsifying Drug Delivery System Enhances Tissue Distribution of Cinnamaldehyde by Altering the Properties of the Mucus Layer.

Oral delivery is considered the preferred route of administration due to its convenience and favorable compliance. However, this delivery often faces difficulties, such as poor solubility, limited absorption, and undesirable stability, especially for some volatile oils. The aim of this study was to develop self-emulsifying drug delivery systems (SEDDS) containing cinnamaldehyde (CA) to overcome these shortcomings. The CA-SEDDS were spherical and smooth with an average size of 14.96 ± 0.18 nm. Differential scanning calorimetry (DSC) and attenuated total reflection by Fourier transform infrared (ATR-FTIR) showed that CA has been successfully loaded into SEDDS. The accumulative release of CA-SEDDS (73.39%) was approximately 2.14-fold that of free CA when using simulated intestinal fluid as the release medium. A scanning electron microscope was used to observe the mucus network structure. Rheological tests found that CA-SEDDS can appropriately enhance the viscosity of the mucus system. We found from tissue distribution studies that CA was more widely distributed in various tissues in the CA-SEDDS group compared to the free CA group. The cinnamaldehyde and cinnamon acid also accumulated more in various tissues in the CA-SEDDS group than in the free CA group, especially in the kidney. These findings hinted that SEDDS exhibited lower irritation, good release, and penetration, which demonstrated great potential for utilizing CA. Our research supports the rational implications of SEDDS in delivering similar volatile substances by improving the solubility, mucus penetration, and stability, resulting in excellent clinical efficacy.

Combining network pharmacology with chromatographic fingerprinting and multicomponent quantitative analysis for the quality evaluation of Moutan Cortex.

In this study, we combined network pharmacology, chromatographic fingerprinting and multicomponent quantitative analysis to evaluate the quality of Moutan Cortex (MC). Specifically, through network pharmacology, we obtained a comprehensive understanding of the active components and pharmacological activities of MC. In addition, the method of establishing fingerprint and multicomponent quantification by ultra high-performance liquid chromatography is convenient and comprehensive, and can more fully reflect the overall distribution of various chemical components. Principal component analysis and discriminant least square analysis were used. The results show that MC plays a synergistic role through multiple targets and pathways. The contents of chemical components in MC from different sources were significantly different. Combining network pharmacology and multicomponent quantitative results, gallic acid, benzoyl paeonol, paeonol, methyl gallate, benzoic acid and paeonol can be used as quality markers for MC quality control. This study provides a comprehensive and reliable strategy for the quality evaluation of MC and determines its quality indicators to ensure the quality of Chinese herbal medicine.

SEDDS facilitate cinnamaldehyde crossing the mucus barrier: The perspective of mucus and Caco-2/HT29 co-culture models.

Self-emulsifying drug delivery systems (SEDDS) have potential applications in the delivery of hydrophobic components. Oral drugs are readily captured and cleared by intestinal mucus, a natural barrier that covers the mucosal epithelium and prevents the entry of foreign substances. In this study, we investigated for the first time the ability of SEDDS to deliver the lipophilic aldehyde cinnamaldehyde (CA-SEDDS) in rat mucus, mucin solution, Caco-2 and Caco-2/HT29 co-culture monolayer systems. CA-SEDDS was characterized by particle size, Zeta potential and the logDSEDDS/release medium. The capacity of CA-SEDDS to enhance mucus permeability was investigated in rat intestinal mucus gel and mucin solution with the period of in 12 h by Transwell® diffusion. We evaluated the potential of CA-SEDDS delivery of CA in a co-culture system of absorptive Caco-2 and mucus-secreting HT29 cells. CA-SEDDS exhibited excellent mucus permeability in mucus and mucin solutions, 5.1- and 2.8-fold higher than the free CA group, respectively. CA-SEDDS penetration increased by 2.5-fold compared with free CA when using the mucus-secreting co-culture cell model as a barrier. The relative oral bioavailability of CA-SEDDS was 242% compared to CA without formulation. These findings suggest that SEDDS exhibited good release and superior mucus permeability, displaying great potential for the future of hydrophobic oral applications.

Physicochemical evaluation and pharmacodynamics of itraconazole-loaded liquid crystal precursor for vaginal delivery.

PURPOSE: To develop a liquid crystal (LC) precursor that can be used as a novel vaginal delivery system for Itraconazole (ITZ) and evaluate its pharmacodynamics. METHODS: The LC precursor was prepared by using phytantriol (PYT) as lipid matrix and N, N-dimethylformamide (DMAC) as solvent. Swelling studies were performed to assess the phase conversion ability. The formulations were characterized by crossed polarized light microscopy (CPLM), small-angle X-ray scattering (SAXS). Moreover, the rheological and in vitro drug release behavior were investigated. Then the vaginal retention time of ITZ in the optimal prescription was evaluated. Finally, the pharmacodynamics studies of the ITZ-loaded LC precursor were performed in a mouse model of vulvovaginal candidiasis (VVC). RESULTS: The LC precursor could transform to LC gels after administration into the vagina. Based on PLM and SAXS, the LC gels, formed after phase-conversion, were cubic LC. The LC precursor was non-Newtonian, while the LC gels exhibited a pseudo-plastic fluid behavior. In vitro release results revealed that F2 (68.0%) had a higher cumulative drug release than that of F1 (59.17%) at 72 h. Most of the LC gels could be retained in the vagina of mice for 24-36 h. Pharmacodynamics studies showed that there was only mild inflammation or no inflammatory stimulation in the control group. The ITZ-loaded LC precursor significantly improved the symptoms of vaginitis in mice and had a better therapeutic effect than that of the positive control group. CONCLUSIONS: The ITZ-loaded LC precursor would be a promising formulation for vaginal drug delivery.

Chemo Proling and Simultaneous Analysis of Different Combinations of Sinomenii Caulis and Ramulus Cinnamomi Using UHPLC-Q-TOF-MS, GC-MS and HPLC Methods.

OBJECTIVE: Sinomenii Caulis (QingFengTeng) and Ramulus Cinnamomi (GuiZhi) are traditional Chinese drugs that have been used for anti-inflammation. In this study, the team plans to find out the material basis of a Chinese herb combination composed of the two herbs with different ratios. METHODS: The extracts of the herbal compound with various ratios obtained from ethanol extraction were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and gas chromatography coupled mass spectrometry to identify the basic chemical compounds. Simultaneously, the contents of the eight main components (sinomenine, magnoflorine, laurifoline, dauricine, coumarin, cinnamyl alcohol, cinnamic acid and cinnamaldehyde) from herb formula were determined by gradient elution by high-performance liquid chromatography. Furthermore, the content of sinomenine and cinnamaldehyde were determined by isocratic elution, respectively. RESULTS: Eighteen compounds in the herb formula were identified by UHPLC-Q-TOF-MS. The components in the GuiZhi are mostly volatile oils and the kinds of compounds isolated from the formula in the ratio of 4:1 were the most. Wherein eight compounds were identified as the main detection targets in the content determination. CONCLUSION: The extraction rate of sinomenine in QingFengTeng was related to the proportion of GuiZhi in the drug pairs. Synchronously, the addition of sinomenine in different proportions also had some influence on the extraction of cinnamaldehyde in GuiZhi. Furthermore, the series of methods was successfully applied to the simultaneous determination of chemical compounds in different samples of QingFengTeng-GuiZhi decoction.

Models to evaluate the barrier properties of mucus during drug diffusion.

Mucus is widely disseminated in the nasal cavity, oral cavity, respiratory tract, eyes, gastrointestinal tract, and reproductive tract to prevent the invasion of pathogenic bacteria and toxins. The mucus layer through its continuous secretion can prevent the passage of macromolecular substances such as pathogenic bacteria and toxins, thereby reducing the occurrence of inflammation. Without a doubt, mucus also hinders oral absorption. The physiological and biochemical properties of intestinal mucus and the different types of mucus barrier models need to be predominated. To find ways to increase the bioavailability of drugs in the future, this article summarizes mucus composition, barrier properties, mucus models, and mucoadhesive/mucopenetrating particles to highlight the information they can afford. Collectively, the review seeks to provide a state-of-the-art roadmap for researchers who must contend with this critical barrier to drug delivery.

The Evaluations of Menthol and Propylene Glycol on the Transdermal Delivery System of Dual Drug-Loaded Lyotropic Liquid Crystalline Gels.

This study aimed to evaluate the effects of two different structural alcohol permeation enhancers (menthol and propylene glycol) on the internal structure and in vitro properties of the dual drug-loaded lyotropic liquid crystalline (LLC) gels. The LLC gels were prepared and characterized by polarized light microscopy, small-angle X-ray scattering, differential scanning calorimetry, attenuated total reflectance-Fourier transform infrared spectrum, and rheology. Based on the results, the inner structure of the gels was QII mesophase and exhibited a pseudoplastic fluid behavior. The level of internal order in the LLC mesophase would be affected by introduced 2 wt% menthol (MEN) and propylene glycol (PG). The in vitro release experiment showed that the release behavior of sinomenine hydrochloride (SH) and cinnamaldehyde (CA) from the LLC system was dominated by Fickian diffusion (n < 0.43). MEN and PG had the opposite effects on the release of hydrophilic SH, while the MEN and PG both increased the release of lipophilic drug CA. Furthermore, in vitro permeation studies indicated that MEN and PG could both improve the skin permeability of SH and CA, and MEN displayed more pronounced enhancement. All the samples showed no skin irritation on the normal rat skin. Collectively, in our research, monoterpenoid MEN exhibited a better penetration-promoting effect than straight-chain fatty alcohol PG on the dual drug-loaded LLC system.

Transdermal Administration of Ibuprofen-Loaded Gel: Preparation, Pharmacokinetic Profile, and Tissue Distribution.

The purpose of this study was to compare the pharmacokinetics and tissue distribution of ibuprofen (IBU) gel in female rats after transdermal administration through the skin of the abdomen and back. IBU was used as the model drug to prepare carbomer gel. After the abdominal and back administration, the concentration of IBU in rat plasma was detected by high-performance liquid chromatography (HPLC). Besides, the contents of IBU in the uterus, heart, liver, spleen, lung, and kidney were detected, respectively, to clarify the distribution characteristics in vivo. Through abdominal route, the AUC0- ∞ (area under the concentration-time curve from time zero to infinity) of uterus was 424.75 µg/g h, which is 3.60 times higher than that of plasma, and was significantly higher than that of other tissues (P < 0.0001). Tmax (peak time) of uterus and plasma was 4 h and 2 h, respectively. Upon transdermal application of IBU to the back, the AUC0-∞ of uterus was 75.47 µg/g h, which is 12.63 times lower than that of plasma, while Tmax of uterus and plasma was not lower than 20 h. These results indicated that IBU entered the blood circulation through abdominal administration in a small amount and mainly of the drug entered the uterus, while IBU entered the blood circulation and redistributed to tissues after absorption through the dorsal skin slowly. IBU could effectively reach the uterus and have a certain targeting through abdominal administration, which provides a prospect for clinical transdermal administration in the treatment of dysmenorrhea.

Dual drug-loaded cubic liquid crystal gels for transdermal delivery: inner structure and percutaneous mechanism evaluations.

The goal of this paper was to develop and evaluate dual component-loaded with the hydrophilic sinomenine hydrochloride (SH) and lipophilic cinnamaldehyde (CA) cubic liquid crystal gels for transdermal delivery. The gels was prepared with a vortex method using phytantriol/water (70:30, w/w) and characterized by polarized light microscopy, small-angle X-ray scattering and rheology. The inner structure of the gels were Pn3m cubic phase and exhibited a pseudoplastic fluid behavior. Furthermore, the in vitro release profile showed that the release behavior of the two drugs from cubic liquid crystal gels conformed to Higuchi equation and were dominated by Fick's diffusion (n < 0.45). The ex vivo penetration experiment indicated that dual components-loaded liquid crystal gels can enhance and extend the skin permeation of these two drugs, especially the ratio of SH to CA is 1: 0.5. Finally, transdermal mechanisms were evaluated using laser scanning confocal microscopy and attenuated total reflectance-fourier transform infrared, hinting that hydrophilic and lipophilic drugs weaken each other's transdermal velocity at the initial stage of penetration. In short, the dual drug-loaded liquid crystal gels was a promising strategy for transdermal applications in treatment of chronic disease.

Self-assembled hexagonal liquid crystalline gels as novel ocular formulation with enhanced topical delivery of pilocarpine nitrate.

The aim of this paper was to develop hexagonal liquid crystalline (HII) gels that can be used as a novel ocular delivery system for pilocarpine nitrate (PN). HII gels were prepared by a vortex method using phytantriol/triglyceride/water (71.15: 3.85: 26, w/w) ternary system. The gels were characterized by crossed polarized light microscopy, small-angle X-ray scattering, differential scanning calorimetry and rheology. And, in vitro drug release behavior and ex vivo corneal permeation were investigated. Finally, preocular residence time evaluation, eye irritation test, histological examination and miotic tests were studied in vivo and compared with carbopol gel. Based on various characterization techniques, the inner structure of the gels were HII mesophase and exhibited a pseudoplastic fluid behaviour. In vitro release results revealed that PN could be released continuously from HII gel over a period of 24 h. The ex vivo apparent permeability coefficient of HII gel was 3.15-fold (P < 0.01) higher than that of the Carbopol gel. Compared with Carbopol gel, HII gel displayed longer residence time on the eyeballs surface using fluorescent labeling technology. Furthermore, the HII gel caused no ocular irritation was estimated by corneal hydration levels, Draize test and histological inspection. Additionally, in vivo miotic study showed that HII gel had a remarkably long-lasting decrease in the pupil diameter of rabbits. In conclusion, HII gels would be a promising sustained-release formulation for ocular drug delivery.

A Novel Phytantriol-Based Lyotropic Liquid Crystalline Gel for Efficient Ophthalmic Delivery of Pilocarpine Nitrate.

The purpose of this paper was to investigate the potential of liquid crystalline (LC) gels for ophthalmic delivery, so as to enhance the bioavailability of pilocarpine nitrate (PN). The gels were prepared by a vortex method using phytantriol and water (in the ratio of 73:27 w/w). Their inner structures were confirmed by crossed polarized light microscopy, small-angle X-ray scattering, attenuated total reflectance-Fourier transform infrared spectrum, and rheology. The in vitro release studies revealed that PN could keep sustained release from the gels over a period of 12 h. The ex vivo apparent permeability coefficient of the gels demonstrated a 3.83-folds (P < 0.05) increase compared with that of eye drops. The corneal hydration levels of the gel maintained in the normal range of 79.46 ± 2.82%, hinting that the gel could be considered non-damaging and safe to the eyes. Furthermore, in vivo residence time evaluation suggested that a better retention performance of LC gel was observed in rabbit's eyes compared to eye drops. In vivo ocular irritation study indicated that LC gel was nonirritant and might be suitable for various eye applications. In conclusion, LC gels might represent a potential ophthalmic delivery strategy to overcome the limitations of eye drops.