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This study aimed to investigate the enhancing effect of muscone on the transdermal penetration of traditional Chinese medicine ingredients and explore its possible mechanism of action. The Franz diffusion cells were employed to investigate the effect of muscone on the transdermal permeation of a series of model drugs with a wide range of log P values. The solubilities at saturation and the stratum corneum(SC)/vehicle partition coefficients of model drugs were measured to evaluate the effect of muscone on drug thermodynamic activities and partition of drugs into SC. Attenuated total reflectance-Fourier transform infrared spectroscopy(ATR-FTIR) was employed to explore the effect of muscone on the molecular structure of SC. The results showed that muscone significantly promoted the transdermal penetration of hydrophilic and lipophilic drugs, and the enhancement ratio(ER) increased with the decrease in the log P. Muscone could interact with the SC lipids to increase the disorder and fluidity of lipid bilayer packing, which improved skin permeability and promoted transdermal absorption of drugs. This study provides a scientific basis for the application of muscone in traditional Chinese medicine topical preparations.
Subject(s)
Animals , Rats , Administration, Cutaneous , Cycloparaffins , Medicine, Chinese Traditional , Permeability , Rats, Sprague-Dawley , Skin/metabolism , Skin AbsorptionABSTRACT
Objective: Taking the volatile oil of Acori Tatarinowii Rhizoma with the effect of anti-senile dementia as model drug to prepare Acori Tatarinowii Rhizoma-volatile oil microemulsion (AO-ME). Methods: The composition of microemulsion was preliminarily determined according to the solubility of volatile oil from Acori Tatarinowii Rhizoma in various solvents. By drawing pseudo-ternary phase diagram, the optimal microemulsion formulation was selected according to the size of particles and microemulsion region, stability of preparations and drug loading. Results: The optimal microemulsion formulation was that volatile oil of Acori Tatarinowii Rhizoma-Cremophor EL-glycerol-water was 6.25:20.83:10.42:62.5. The average particle size of AO-ME was (30.5 ± 0.2) nm with a polydispersity index of 0.150 ± 0.002. The viscosity value of AO-ME was (2.80 ± 0.21) mPa∙s. In vitro transdermal rate of AO-ME was (1 288.76 ± 16.20) μg/(cm2∙h), measured in β-asarone. Compared with ordinary emulsion, the transdermal rate of AO-ME was increased 14 times. The ciliary toxicity test of toad showed that the preparation had no significant toxicity. Conclusion: The preparation of AO-ME was prepared with stable physicochemical properties, good transdermal properties, and low toxicity to nasal mucosa cilia.
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The aim of this study was to investigate the transdermal penetration enhancement effect of wintergreen oil and its action mechanisms. The in vitro transdermal tests were carried out to study the transdermal penetration enhancement effect of wintergreen oil by using osthole and geniposide as the lipophilic and hydriphilic model drugs. Fourier-transform infrared spectroscopy was used to investigate the effect of wintergreen oil on the molecular structure of rat stratum corneum, and the scanning electron microscope was employed to observe the change of rat skin surface after treatment by the oil. The wintergreen oil at proper concentrations could effectively promote the transdermal permeation of osthole and geniposide, and exhibited better penetration-enhancing activity for the lipophilic osthole, close to the commonly used classical penetration enhancer azone. The infrared spectroscopy study and scanning electron microscope showed that wintergreen oil mainly acted on the stratum corneum lipids, reduced dense stratum corneum, and reduced the skin barrier function. Thus, the wintergreen oil could effectively facilitate the transdermal absorption of the lipophilic and hydrophilic drugs, resulting from the lowed skin barrier function.
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OBJECTIVE: To prepare and characterize sinomenine liquid crystal gel, study the rheological properties and in vitro transdermal properties and compare with sinomenine ointment and sinomenine hydrophilic gel. METHODS: Sinomenine liquid crystal gel was prepared by using phytanetriol-water system and then characterized by polarized light microscope(PLM)and small angle X-ray diffraction(SAXS). Using DHR-2 rheometer, the rheological properties of sinomenine liquid crystal gel were investigated and compared with those of sinomenine ointment and sinomenine hydrophilic gel. Modified Franz diffusion cell was used for in vitro transdermal experiment and the in vitro transdermal properties were compared with sinomenine hydrogels and ointments. RESULTS: The appearance of sinomenine liquid crystal gel was colorless, clear and transparent, and showed dark field under PLM. SAXS showed cubic phase. The rheological parameters were good. The steady-state infiltration rates of sinomenine liquid crystal gel, ointment and hydrophilic gel were 153.93, 119.99, and 106.89 μg·cm-2·h-1, and their 48 h cumulative permeation amounts(%)were 93.76%, 91.55%, and 87.60%, respectively. CONCLUSION: PLM and SAXS can be used to characterize the liquid crystal gel.The prepared sinomenine liquid crystal gel has good appearance and suitable rheology, and its infiltration rate and 48 h cumulative permeation amount are superior to those of ointment and hydrophilic gel, which provides theoretical reference for sinomenine percutaneous administration.
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The results of previous studies showed potential correlations between the penetration enhancement effect of essential oils and the drug properties of traditional Chinese medicine based on the data mining method. As chemical composition is the material basis of drug properties of traditional Chinese medicine, this article further analyzed the correlation between the chemical composition of essential oils and the drug properties. Firstly, essential oils were extracted by steam distillation, and then physicochemical parameters of essential oils, such as relative density and refractive index, were measured. The chemical components of 20 essential oils were analyzed by GC-MS, and divided into 12 categories according to skeleton features and functional groups. Finally, Logistic regression analysis was applied to reveal the correlations. The results proved that five flavors, four tastes and channel tropisms showed the correlation with chemical composition of essential oils (P<0.05). In conclusion, there were obvious correlations and regularity between the drug properties of traditional Chinese medicine and the chemical composition of essential oils.
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The aim of this paper was to investigate and compare the penetration-enhancing characteristics of menthol and essential oil from Mentha haplocalyx(M.haplocalyx oil) on the transdermal absorption of the complex traditional Chinese medicine(TCM) components. A series of TCM components were selected as model drugs based on their lipophilicity (logP value), namely osthole(OT, logP=3.85), tetramethylpyrazine(TMP, logP=2.34), ferulic acid(FA, logP=1.26), puerarin(PR, logP=-0.35) and geniposide(GP, logP=-1.01), in order to simply and characterize the TCM complex components system. Transdermal experiment in vitro was employed to investigate and compare the penetration-enhancing characteristics of menthol and M.haplocalyx oil on the transdermal absorption of these model drugs. Meanwhile, Fourier transform infrared spectroscopy(FTIR) was used to further compare the effect of menthol and M. haplocalyx oil on the molecular structure of stratum corneum(SC). The results showed that both of menthol and M.haplocalyx oil at proper concentration could promote the transdermal absorption of the selected model drugs. After application of menthol, the drug logP values gradually tended to have negative linear relationship with the logarithm of penetration enhancement ratio(ER); while after application of M.haplocalyx oil, the logP values tended to have parabolic relationship with the logarithm of ER. However, both menthol and M.haplocalyx oil exhibited higher efficiency for the drugs with relative low lgP value(ie hydrophilic drugs), with similar penetration-enhancing characteristics between these two. Infrared spectroscopy results showed that menthol and M.haplocalyx oil could affect the skin barrier functions mainly via stratum corneum lipids, with similar effect intensity, and this was consistent with the results of transdermal experiment in vitro. Thus, Menthol had similar penetration-enhancing characteristics with M.haplocalyx oil, and had same effect on the SC molecular structure. Therefore, as transdermal penetration enhancer, the menthol with single composition could be considered to replace M.haplocalyx oil with complex compositions.
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Objective:To study the in vitro and in vivo transdermal penetration of testosterone undecanoate ( TU) binary ethosomes gel. Methods:TU binary ethosomes were prepared by an ethanol injection method, and using carbopol 941 as the gel base, TU binary ethosomes gel was prepared. Using mouse skin as the barrier, Franz cells were applied to explore the in vitro transdermal penetration of TU binary ethosomes and the gel. Rats were used as the animals, and TU binary ethosomes and the gel was respectively administrated on the back skin. At the predetermined time points, plasma samples were withdrawn to detect the concentration of TU, and the main pharmacokinetics parameters were calculated. Results: The in vitro transdermal penetration of TU binary ethosomes and the gel was both fitted first-order equation:Q=8. 68t+6. 78(r=0. 998 2) and Q=6. 09t+3. 09(r=0. 999 3), and the stable penetration rate was 8. 68 μg·cm-2 ·h-1 and 6. 09μg·cm-2 ·h-1 , respectively. After the 24-hour penetration, the residual amount in skin of TU binary ethosomes and the gel was (208. 80 ± 55. 26)μg·g-1 and (225. 60 ± 38. 90)μg·g-1 , respectively. The main pharmacokinet-ics parameters of TU binary ethosomes and the gel were Cmax of(18.50 ±2.75)mg·L-1 and(20.80 ±2.42)mg·L-1, tmax of(6.20 ± 0. 14)h and(9. 54 ± 0. 52)h, and AUC0-48h of(336. 74 ± 2. 05)h and(486. 30 ± 1. 68)h. Conclusion:TU binary ethosomes and the gel both exhibit promising in vitro transdermal penetration, and the gel shows better sustained release property.
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Objective To investigate the influence of β-cyclodextrin (β-CD ) inclusion and its cataplasma on the transdermal permeability of volatile oil extracted from Chuanxiong Rhizoma and Asari Radix et Rhizoma by means of percutaneous penetration test of four preparations containing of the volatile oil. Methods Using the modified Franz diffusion pool as equipment,with 40% ethanol solution as absorption solution and SD rat skin coated with the volatile oil,aβ-CD inclusion complex of the volatile oil,a cataplasma of theβ-CD inclusion complex of the volatile oil,and a cataplasma of the mixture of the volatile oil andβ-CD,respectively,as experimental skin,the transdermal penetration test was carried out.The cumulative penetrative amounts of volatile oil in the absorption liquid were measured by GC-MS in order to evaluate the differences in the percutaneous permeability. Results The percutaneous penetration rate constant size order of four preparations containing the volatile oil is as follows:the volatile oil directly coated on the skin > the cataplasma of β-CD inclusion complex of the volatile oil > the β-CD inclusion complex of the volatile oil directly coated on the skin > the cataplasma of the mixture of the volatile oil and β-CD. Conclusion The compositions of the volatile oil retrieved from the β-CD inclusion complex are no significant changes. The percutaneous permeability of the cataplasma of β-CD inclusion complex of the volatile oil is better than that of the cataplasma of the mixture of volatile oil and β-CD.
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Objective To study preparation of micronized Shuanghuangpo hydrogel patch and its characteristics of transdermal penetration in vitro. Methods Micronized Shuanghuangpo hydrogel patch was prepared with some macromolecular water-soluble materials as gel base.The content of berberine was determined by HPLC method.Its transdermal penetration in vitro was determined according to the method of Chinese Pharmacopoeia 2010 edition. The rat skin penetration test in vitro was performed by modified Franz diffusion cell method. Results The hydrogel patch had constant content of berberine. Its release property in vitro conformed to Higuchi equation. The penetration of berberine in the hydrogel patch through the rat skin followed zero-order dynamics in 12 h.Its release rate was 7.934μg??(cm2)-1??h1/2 and percutaneous rate was 0.571μg??(cm2)-1??h-1. Conclusion The micronized Shuanghuangpo hydrogel patch is a new transdermal agent with sustained release property.
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Objective:To study the in vitro and in vivo transdermal enhancement of one kind of arginine oligomer-chitosan ( CS-R9). Methods: In vitro mouse skin as the barrier, Franz diffusion cells were used to study the transdermal property of tinidazole ( TNZ) solution in vitro enhanced by CS-R9 using TNZ solution as the negative control and TNZ solution with Azone as the positive control. The rats were randomly divided into three groups, TNZ solution group ( the negative group) , TNZ solution with Azone group (the positive group) and TNZ solution with CS-R9 group. At the predetermined time intervals, 0. 5 ml blood was withdrawn from the rats and TNZ concentration was detected by HPLC to evaluate the enhancement of CS-R9 on TNZ in vivo. Results:Compared with the negative group, CS-R9 had significant enhancement on TNZ trandermal penetration in vitro(P 0. 05). The in vivo results showed CS-R9 exhibited similar transdermal enhancement on TNZ as Azone at the same concentration (P>0. 05), and CS-R9 had sustalned-release property. Conclusion: CS-R9 has promising transdermal en-hancement on TNZ, which is valuable to be studied further.
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Objective:To study the effect of molecular weight and degree of substitution (DS) of chitosan-poly-arginine (CS-R9) on transdermal penetration enhancement in vitro. Methods:Low molecular CS, medium molecular CS or high molecular CS was respectively used to synthesize CS-R9 with different molecular weight (LCS-R9-1, MCS-R9 and HCS-R9). Low molecular CS was used to synthesize CS-R9 with various degree of substitution by changing the mole ratio between R9 and CS (LCS-R9-1, LCS-R9-2 and LCS-R9-3). The in vitro transdermal penetration enhancement of the different CS-R9 on tinidazole ( TNZ) was studied using Franz diffusion cells. Results:According to the results of FTIR and 1 H-NMR, a series of target CS-R9 were synthesized including LCS-R9-1 with the DS of 2. 30, MCS-R9 with the DS of 2. 17, HCS-R9 with the DS of 2. 20, LCS-R9-2 with the DS of 8. 05 and LCS-R9-3 with the DS of 15. 87. Compared with the blank control group, Azone group, LCS group, R9 group and LCS+R9 group, LCS-R9-1 could enhance the in vitro transdermal penetration of TNZ significantly (P0. 05). When the molecular weight of CS was unchanged, the effect was increased with the rise of DS in the first 21h, however, after that, the effect was decreased with the rise of DS. Conclusion:Molecular weight and DS both have significant effect on the in vitro transdermal penetration enhancement of CS-R9, and it is valuable to further study the in vivo transdermal penetration enhancement of CS-R9 and underlying mechanisms.
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Pharmaceutical excipients for topical use may contain impurities, which are often neglected from a toxicity qualification viewpoint. The possible impurities in the most frequently used topical excipients were evaluated in-silico for their toxicity hazard. Acetol, an impurity likely present in different topical pharmaceutical excipients such as propylene glycol and glycerol, was withheld for the evaluation of its health risk after dermal exposure. An ex-vivo in-vitro permeation study using human skin in a Franz Diffusion Cell set-up and GC as quantification methodology showed a significant skin penetration with an overall Kp value of 1.82 ? 10 ? 3 cm/h. Using these data, limit specifications after application of a dermal pharmaceutical product were estimated. Based on the TTC approach of Cramer class I substances, i.e. 1800 mg/(day?person), the toxicity-qualified specification limits of acetol in topical excipients were calculated to be 90 mg/mL and 180 mg/mL for propylene glycol and glycerol, respectively.
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Objective: To prepare and optimize the prescription of betulinic acid (BA) ethosomes modified by sodium deoxycholate (SDC) and then to investigate its transdermal penetration as carrier of BA. Methods: The BA ethosomes modified by SDC were prepared by the ethanol injection method. The encapsulation efficiency (EE) was considered as the evaluation index to optimize the prescription of the ethosomes by orthogonal design, and the shape and particle size of the optimized ethosomes were analyzed. The in vitro transdermal absorption of BA was evaluated using Franz diffusion cells. The accumulated permeation amounts and permeation rate of liposomes, ethosomes, and BA ethosomes modified by SDC were compared. Results: The best formulation consisted of soybean lecithin-SDC-BC (18:1:1) and 35% ethanol. The average EE and the particle size were (93.8 ± 1.6)% and (102.3 ± 3.6) nm, respectively. The accumulated permeation amount of BA ethosomes modified by SDC in 12 h was (99.62 ± 9.44) μg/cm2, which was 1.67, 3.85, and 8.33 times of ethosomes, liposomes, and satuated solution containing 10% isopropanol, respectively. Conclusion: The BA ethosomes, modified by SDC with high EE, obviously enhance the percutaneous absorption of BA and might be one of the most perspective percutaneous preparations.
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Objective: To prepare perillyl alcohol ointment (PAO) and to investigate its properties and transdermal absorption behavior. Methods: The emulsion method was used to prepare PAO. The morphology, stability, and in vitro release were examined, respectively. The transdermal absorption of PAO was evaluated using Franz diffusion cells and the perillyl alcohol content was determined by HPLC. Results: The optimal prescription of PAO was perillyl alcohol, stearic acid, glyceryl monostearate, white vaseline, lanolin, liquid paraffin, triethanolamine, glycerine, and ethylparaben. The product was a pale yellow semi-solid oil-in-water emulsion with a uniform appearance. The content of perillyl alcohol in ointment was (2.89 ± 0.17)%, the release accumulation in vitro achieved 61.25% in 12 h, and the percutaneous penetration rate was 9.42 μg/(cm2·h). The ointment was not stratified after the centrifugation at 3500 r/min for 30 min, and the product was fairly stable under the condition of storing at 0 and 40°C for 30 d. Conclusion: The prepared PAO with increased skin retention amount could be developed into a novel preparation of perillyl alcohol for focal administration.