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.

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.

The Effect of Prescription on the Framework of Lipid Matrix and In Vitro Properties.

PURPOSE: To clarify the inner framework and relative properties in vitro of Lyotropic liquid crystal (LLC) based on various prescriptions by using hydrophilic sinomenine hydrochloride (SH) and lipophilic cinnamaldehyde (CA) as model drugs. METHODS: Phase structures were checked by polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). Rheological studies and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) analysis were carried out to reveal their molecular interactions. In vitro release and skin permeation were conducted by Franz diffusion cell. RESULTS: PLM and SAXS showed double diamond cubic crystal. All the samples displayed characteristics of non-Newtonian fluid, and the molecular interactions increased with the reducing water. ATRFTIR showed that the strongest strength of hydrogen bond emerged in the formulation with 32% water. Released SH of S2 and S3 arrived over 80%, while S1 only reached 45%, and that of CA was about 23%. Water-rich prescription gave higher percutaneous penetration for hydrophilic drugs, whereas no significant difference existed in CA permeation. CONCLUSION: Proportion of Phytantriol to water determined the LLC assembling and affected the dissolving status of hydrophilic substance, thereby impacting on the location sites of guest molecular interactions among the substances, rheology properties, and finally the release and penetration behavior in vitro. Adjusting the basic prescription was the key to obtain satisfactory percutaneous delivery and stability for LLC carrying multi-therapeutic agents.

Phytantriol-based lyotropic liquid crystal as a transdermal delivery system.

The purpose of this study was examined the feasibility of using phytantriol-based cubic and hexagonal liquid crystal preparation for the percutaneous administration of trans­cinnamaldehyde (TCA). TCA-loaded lyotropic liquid crystal formulations were prepared and characterized, their skin permeability in vitro and in vivo was evaluated. Preliminary pharmacodynamics were also investigated in adjuvant arthritics (AA) rats. The formulations were identified respectively as cubic and hexagonal structure. The in vitro permeability study exhibited that both cubic and hexagonal liquid crystal improved the cumulative permeation quantity and permeation rates of TCA compared with home-made gel. The results of an in vivo transdermal permeability experiment showed that the area under the curve [AUC(0-∞)] of the hexagonal and cubic liquid crystal was 1.62 and 1.53 times higher than that of the gel group, respectively. Preliminary pharmacodynamics studies indicated that the group of high-dose TCA-loaded (200 mg·kg-1) hexagonal liquid crystal was shown to inhibit the paw swelling of AA rats, improve synovial hyperplasia and inflammatory cell infiltration, and down-regulate the levels of serum interleukin (IL)­1ß and tumor necrosis factor (TNF)­α. Furthermore, there was no significant difference in the anti-inflammatory effects of TCA-loaded hexagonal liquid crystal and the commercially available product Voltaren® emulgel®. Thus, hexagonal liquid crystal was considered as an effective delivery system for TCA.

On the Structure and Transdermal Profile of Liquid Crystals Based on Phytantriol.

BACKGROUND: There has been a growing concern in transdermal drug technology over the past several decades. As a novel transdermal delivery system, Lyotropic liquid crystals (LLC) still face challenges such as drug loading, limited drug permeation and instability of systems. LLC system is so sensitive that a very subtle change in composition may induce a phase transformation or conversion of spatial configuration, and result in a diverse percutaneous delivery subsequently. OBJECTIVE: To find out the effects of hydrophilic and lipophilic components on the structure and transdermal properties of LLCs, hydrophilic sinomenine hydrochloride (SH) and lipophilic cinnamaldehyde (CA) was chosen as a model drug and a skin permeation enhancer, respectively, several formulations were prepared and compared. METHOD: The structure of LLC was evaluated by visual observation, Cross-polarizing light microscopy (CPLM) and Small angle X-ray diffraction (SAXS). The Franz diffusion cell was applied to investigate its skin penetration of SH across the rat skins. Fourier transform infrared spectroscopy (FTIR) was recorded to evaluate the intermolecular interaction between the LC samples and stratum corneum (SC). CONCLUSION: The results showed that a controlled transdermal process might be obtained by adjusting the ratios of different drugs or loading doses when LLCs with dual-components were applied.

[Rheological properties of sinomenine in situ liquid crystal as liquid embolic agent].

Three different kinds of sinomenine in situ liquid crystal were prepared for different prescriptions, to investigate the rheological properties before and after in situ treatment and evaluate its feasibility for embolization. Rheological experiments were carried out with cone plate fixtures. Both the steady-state rheological and non-steady-state rheological properties of in-situ gels and the swelling gels were studied and compared. Steady-state rheological study results showed that all the three liquid embolic agents were non-newtonian fluid before and after in situ treatment, which would become less ropy when they were pressed with shear stress; their viscosities differed by 2-5 orders of magnitude. It had a yield value of about 10 Pa before in situ treatment and about 4 500 Pa after in situ treatment. All the six systems had thixotropy while their dynamic viscosities were not influenced by the shear rate, all less than 0.3 Pa·s before in situ treatment more than 1 Pa·s after in situ treatment, differing by an order of magnitude. The results of temperature sweeping showed a slight decrease with a steady rate in viscosity within the range of 10-50 °C, differing by 3-4 orders of magnitude. The results of unsteady rheology showed that there was no obvious linear viscoelastic region in the three kinds of agents, indicating the properties of liquid. After in situ treatment, their linear viscoelastic range γ<1% (No.3 was 5%), and their elastic modulus G' was larger than the viscous modulus G", indicating the properties of solid. Frequency scanning results showed that for the systems at low frequencies, G">G', system viscosity in a dominant position; while at high frequencies, G'>G", system elasticity in a dominant position. The results of compound viscosity test also proved that the liquid embolic agent in situ can form a cubic liquid crystal (the structure of No. 3 was destroyed after in situ treatment). The DHR-2 rheometer was used to investigate the rheological properties of in situ gels with three different prescriptions. The method is simple and the result is reliable, which can provide more theoretical reference for the in vitro evaluation and practical application of the product.

Synthesis and evaluation of benzylisoquinoline derivatives for their inhibition on pancreatic lipase and preadipocyte proliferation.

The present study was designed to synthesize and evaluate a series of benzylisoquinoline derivatives. These compounds were synthesized by Bischler-Napieralski cyclization to yield 1-benzyl-3,4-dihydroisoquinolines, and the products were obtained by reductions. All these compounds were identified by MS, (1)H NMR and (13)C NMR. The inhibitory activities on pancreatic lipase and preadipocyte proliferation for the synthesized compounds and alkaloids from Nulembo nucifera were assessed in vitro. Most of the compounds showed inhibitory activities on both pancreatic lipase and preadipocyte proliferation. Particularly, compounds 7p-7u and 9d-9f exhibited significant inhibitory activity on pancreatic lipase while compounds 7c, 7d, 7f, 7g, 7i, and 7j potently inhibited the proliferation of 3T3-L1 preadipocytes. Our results provided a basis for future evaluation and development of these compounds as leads for therapeutics for human diseases.

[Purification of total flavonoids from the extracts of Thesium Chinese with macroporous adsorption resin].

OBJECTIVE: To optimize the process parameters for purifying total flavonoids from Thesium chinese with D101 macroporous adsorption resin. METHODS: Purification technology of total flavonoids from the extracts of Thesium chinese was investigated by dynamic adsorption method with the transfer rates and the purity of total flavonoids as indexes. RESULTS: The optimal purifying conditions were as follows: sample concentration was 2.259 mg/mL with a speed of 1 BV/h, eluent concentration was 70% alcohol with a speed of 1BV/h. After purification, the transfer rate of total flavonoids was 94.44% and the purity of total flavonoids achieved 12.45%, which was 4 times of that by coarse extraction (2.91%). CONCLUSION: The purification technology is simple, stable and can significantly improve the contents of total flavoids in extracts.