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To establish a determination method for the contents of ammonium glycyrrhetate,nardosinone,and curcumin in transdermal receptor liquid of Baimai Ointment,and investigate the percutaneous permeability of Baimai Ointment and the effects of two kinds of penetration enhancers on percutaneous absorption of three components. The contents of ammonium glycyrrhetate,nardosinone,and curcumin in transdermal receptor liquid were determined by high pressure liquid chromatography( HPLC). The vertical modified Franz diffusion cell was used to perform a transdermal experiment in vitro with the abdominal skin of mice( treated and untreated). The transdermal receptor liquid was preferably used to investigate the transdermal absorption rule of the Baimai Ointment and the effect of the penetration enhancer. The results showed that the comprehensive solubility of PEG-ET-NS( 3 ∶3 ∶4) was best among three types of receptor liquid PG-ET-NS( 3 ∶3 ∶4),PEG-ET-NS( 3 ∶3 ∶4),ET-NS( 3 ∶7). PEG-ET-NS was used as the receptor liquid for in vitro transdermal experiments. The cumulative permeation area of ammonium glycyrrhetate,nardosinone and curcumin within 24 h was 5. 73,18. 99,0. 38 μg·cm~(-2)respectively. Taking QEFand ER as comprehensive evaluation indicators of permeation performance,the comprehensive penetration-promoting performance of ammonium glycyrrhizinate: 3% PEG 400-ethanol-normal saline ≈ 1. 19 times( 3%azone) = 1. 94 times( blank); comprehensive penetration-promoting performance of nardosinone: 3% PEG 400-ethanol-normal saline≈1. 28 times( 3% azone) = 1. 37 times( blank); the comprehensive penetration performance of curcumin: 3% PEG 400-ethanol-normal saline≈1. 77 times( 3% azone) ≈3. 42 times( blank). The comprehensive penetration enhancement properties of the two penetration enhancers were as follows: 3% PEG 400-ethanol-normal saline>3%azone>blank. The transdermal absorption curve of ammonium glycyrrhetate,nardosinone and curcumin in Baimai Ointment were consistent with the zero-order equation,indicating that the transdermal absorption process was irrelevant to the concentration of three components,and its was a diffusion process. This experiment provides reference for the study of ointment transdermal preparations.
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Animals , Mice , Administration, Cutaneous , Ointments , Pharmacokinetics , Permeability , Skin , Skin AbsorptionABSTRACT
Objective To evaluate the skin irritation of eucalyptus oil and its in vivo transdermal penetration enhancement properties by using the cutaneous microdialysis technique. Methods The CCK-8 assay was used to measure the toxicity of eucalyptus oil on HaCaT cells, and the TEWL values of the rat skin was determined to investigate the effect of eucalyptus oil on the skin integrity and irritation. Ligustrazine and geniposide were chosen as lipophilic and hydrophilic model drugs, respectively, and their microdialysis probe in vivo recoveries were determined using the retrodialysis method. After treatment with eucalyptus oil, the skin pharmacodynamics behaviors of two model drugs were investigated to evaluate its penetration-enhancement activity. Results The cytotoxicity test revealed there IC50 value of eucalyptus oil to HaCaT cells was 2.452 mmol/L, which was significantly higher than that of chemical penetration enhancer Azone (IC50, 0.266 mmol/L). Meanwhile, the eucalyptus oil had a certain impact on the rat skin TEWL values, but it was weaker than Azone, this implied that the eucalyptus oil had a mild skin irritation. The in vivo transdermal microdialysis tests revealed that the enhancement ratios (ER) of ligustrazine and geniposide were 11.40 and 13.79, respectively, indicating that eucalyptus oil could effectively facilitate the transdermal permeation of both of lipophilic and hydrophilic drugs. Although the penetration enhancement property was generally weaker than Azone, the ER value of eucalyptus oil was closely approximate to Azone. Conclusion The eucalyptus oil could promote the transdermal permeation of both lipophilic and hydrophilic drugs with mild skin irritation, which provided the data support for its application in topical preparation.
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AIM To prepare Guizhi Fuling transdermal patch.METHODS With kinds of pressure-sensitive adhesive and penetration enhancer,kind and consumption of solvent,drug loading as influencing factors,appearance,formability and viscidity of patch,extract dispersion as evaluation indices,single factor test was applied to optimizing the preparation.And subsequent in vitro transdermal absorption test was performed to investigate the steady-state permeation rates of paeoniflorin,cinnamic acid and paeonol onto rat skins.RESULTS The optimal conditions were determined to be Duro-Tak 87-2677 polyacrylate pressure-sensitive adhesive (matrix),1 ∶ 0.5 for ratio of extract to propanediol (solvent),3％ azone as a penetration enhancer,and 20％ for drug loading,the obtained transdermal patch demonstrated both ideal initial adhesion force and holding adhesion force.These three constituents' average transdermal rates were 34.32,1.684,72.90 μg/(cm2 · h) with the average release rates of 26.81,1.523,111.8 μg/(cm2 · h),respectively,whose in vitro transdermal permeation curves conformed to Higuchi equation.CONCLUSION Guizhi Fuling transdermal patch processed with simple and stable preparation technique exhibits good in vitro transdermal permeation performance.
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Objective:To study the preparation and in vitro release and transdermal absorption of compound film forming gel. Methods:The compound film forming gel was made from new types of film-forming materials. The in vitro release rate was determined by Franz diffusion cells. Results:The in vitro release rate of mupirocin and dyclonine from the compound film forming gel was 81.34% and 88.46%,the transdermal cumulative release amount was(192.73 ± 0.45) μg·cm-2and(103.58 ± 0.66) μg·cm-2,and the skin retention was (419.81 ± 1.48) μg·cm-2and (212.07 ± 1.81) μg·cm-2, respectively. Conclusion: The release of drug is nearly complete. The transdermal absorption test shows that about 30.26% mupirocin and 32.53% dyclonine can pass through skin, and about 65.91% mupirocin and 66.59% dyclonine are stored in skin. The preparation not only plays the role of bacteriostasis,but also promotes wound healing and analgesia.
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To establish a determination method for the contents of paeonol, eugenol and piperine in receptor liquid and to research the transdermal permeability of Huoxue Zhitong patch. The contents of paeonol, eugenol and piperine in receptor liquid were determined by high pressure liquid chromatography(HPLC); and the receptor liquid was optimized by taking accumulative amount penetrated within 24 hours, percutaneous permeation rate and skin irritation as indexes. In vitro Franz diffusion experiment was applied to assess the percutaneous penetration characteristics and regularity of Huoxue Zhitong patch. The results showed that the accumulative penetration amount and penetration rate by using PEG 400-ethanol-normal saline 3∶3∶4 as receptor liquid were higher than those by using propylene glycol∶ethanol∶normal saline 3∶3∶4 and ethanol-normal saline 3∶7, the and skin irritation of PEG 400-ethanol-normal saline 3∶3∶4 was smaller than propylene glycol:ethanol: normal saline 3∶3∶4. Results of percutaneous permeability experiments displayed that the accumulative amount penetrated of paeonol, eugenol and piperine within 24 hours was 2.84, 19.9, and 0.753 μg•cm⁻² respectively in Huoxue Zhitong patch and the penetration rate was 0.18, 1.22, and 0.02 μg•cm⁻²•h⁻¹ respectively. Thus, the permeation of paeonol, eugenol and piperine through the skin was a diffusion process, which was irrelevant to their content in patch.
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Objective:To study the kinetics of transdermal absorption of volatile oil from Angelica slinesis in fetal skin and investi-gate the mechanism of penetration enhancement in terms of morphology. Methods: Franz diffusion cells were used to investigate the transdermal characteristics in vitro. The content of ligustilide was determined by HPLC, and the cumulative permeation amount per unit area and rate constant of ligustilide were calculated. The effects of volatile oil from Angelica slinesis on skin ultrastructure was observed by a scanning electron microscope and a transmission electron microscope. Results:The kinetics of volatile oil at different concentra-tions was all in accordance with Higuchi equations. The ultrastucture changes of fetal skin under the scanning electron microscope were as follows:the wrinkles on skin surface increased, some areas of stratum corneum peeled off and turnovered like worn-out cotton pad-ding, the follicular orifice was enlarged, and the cuticles of the hair shaft dropped off and became thinner. The changes of fetal skin ul-trastucture under the transmission electron microscope were as follows:stratum corneum cells peeled off, the cell junction in basal lam-ina and stratum spinosum were broken, and the intercellular space was enlarged. Conclusion: The volatile oil from Angelica slinesis has good transdermal permeability. Its enhancement mechanism of transdermal drug absorption is closely related with the effects on skin ultrastructure, which can change the structure of stratum corneum to increase the cell gaps resulting in enhancing drug penetration.
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Objective:To study the in vitro transdermal permeability of nifedipine nanoemulsion ( NFNE) containing different per-meation enhancers to lay foundation for the development of transdermal nifedipine preparation. Methods: Franz diffusion cells were used to study the transdermal enhancement of NFNE with different transdermal enhancers ( Azone, oleic acid, TMC20, TMC40, TMC60). Results:The in vitro transdermal effect of NFNE was better than that of nifedipine (NF). The order of in vitro transdermal permeation enhancement was as follows: azone > oleic acid > TMC60 > TMC40 > TMC20, while the water-soluble transdermal permeation enhancers had faster effect. Conclusion:For NFNE, fat-soluble transdermal permeation enhancers have better effect.
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To increase the permeation and retention of isopsoralen in skin, and improve its bioavailability.Isopsoralen loaded nanostructure liquid carrier (IPRN-NLC) was prepared by high pressure homogenization andoptimized by orthogonal experiment with the encapsulation efficiency, drug loading and average particle size as the evaluation indexes. The in vitro transdermal permeation of IPRN-NLC was evaluated by Franze diffusion cells.The results showed that solid-liquid lipid ratio of optimum IPRN-NLC formulation was 7∶3,drug-lipid ratio of 1∶30, 1% surfactant. Under these conditions, IPRN-NLC had an average encapsulation of （90.25±0.73）%,drug loading of （1.56±0.27）% and an average particle size of (305±1.57) nm.The in vitro transdermal permeation results showed that IPRN-NLC could increase the amount of IPRN permeated though skin, with 3 times of the epidermal retention as compared with IPRN solution. From the results we can know that the IPRN-NLC prepared by high pressure homogenization can improve the permeation andaccumulation of IPRN in the skin, with wide application prospects in the field of transdermal administration.
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To prepare tanshinone ⅡA loaded nanostructured lipid carrier (Tan ⅡA-NLC), and study its in vitro transdermal permeation characteristics. The Tan ⅡA-NLC was prepared by high pressure homogenization technology and optimized by Box-Behnken design-response surface method, and it was characterized in terms of morphology, particle size, zeta potention, et al. The transdermal permeation of Tan ⅡA-NLC was evaluated by using Franz diffusion cells. The results showed that, the optimal formulation was as follows: drug/lipid materials ratio 88, GMS/MCT ratio 2, emulsifier concentration 1%, average particle size (182±14) nm, polydispersity index PDI (0.190 6±0.024 5), zeta potential (－27.8± 5.4) mV, encapsulation efficiency EE (86.44%±9.26%) and drug loading DL (0.98%±0.18%), respectively. The in vitro transdermal permeation results showed that as compared with Tan ⅡA solution, Tan ⅡA-NLC had lower transdermal permeation amount after applying drug for 24 h, but its retention in the epidermis was 3.18 times that of solution. These results indicated that the prepared Tan ⅡA-NLC could effectively increase the regention of Tan ⅡA in the epidermis, and had a broad application prospect.
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To prepare the liposomes and transfersomes of brucine, characterize their pharmaceutical properties, and compare their in vitro transdermal permeation properties. The liposomes and transfersomes of brucine were prepared by ammonium sulfate gradient method to investigate their pharmaceutical properties such as the particle size, encapsulation efficiency and deformation. The transdermal permeation properties in vitro of liposome and transfersomes from different prescriptions were compared by using modified Franz-diffustion cells with rat skin as the transdermal barrier. The results showed that the particle size of liposomes and transfersomes for brucine ranged from 100 nm to 150 nm, with even distribution for particle size. As compared with the soybean phosphatidylcholine (SPC) transfersomes, the encapsulation efficiency of complex phospholipid transfersomes was significantly improved. The deformation index of complex phospholipid transfersomes in brucine was 2.09 times and 1.76 times as much as SPC liposomes and SPC transfersomes respectively. The steady state flux of complex phospholipid transfersomes was 3.43 times and 1.41 times as much as SPC liposomes and SPC transfersomes. The steady state flux of the physical mixture of brucine and blank complex phospholipid transfersomes was 2.20 times as much as brucine solution. The concentration of complex phospholipid had effect on transdermal permeation of blank transfersomes. In conclusion, as compared with liposomes, the permeation behavior of transfersomes was significantly improved; complex phospholipid technology can improve the membrane phase behavior of transfersomes, and further improve the deformation index and transdermal flux of transfersomes; in addition, blank transfersomes have promoting effect on transdermal absorption of brucine.
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The Aconiti Radix Cocta gel and Aconiti Radix Cocta combined with Paeoniae Radix Alba gel were administered to mice. Physiological saline was taken as perfusate. The perfusion rate was 2 μL•min⁻¹ and the microdialysis samples were collected every 0.5 h intervals for eight times. The six aconitine alkaloids concentration in perfusate were determined by HPLC-MS/MS. The concentration-time curves were plotted, and the pharmacokinetic parameters were calculated and analyzed by SPSS. The effects of Paeoniae Radix Alba on transdermal permeation role of six aconitine alkaloids in herb couple of Paeoniae Radix Alba-Aconiti Radix Cocta were investigated. According to the results, Tmax of the three mono-ester aconitum alkaloids of Aconiti Radix Cocta combined with Paeoniae Radix Alba groups were shortened, meanwhile, Cmax and AUC of benzoylaconine and benzoylhypaconine were increased. However, AUC of the three diester-type alkaloids were reduced, with Tmax of hypaconitine prolonged and Cmax lowered. The study suggested that the combined administration of Aconiti Radix Cocta and Paeoniae Radix Alba promoted the transdermal permeation of mono-ester aconitum alkaloids, and inhibited the absorption of parts of diester-type alkaloids. This study proved the decreasing toxicity and increasing efficacy of the combination of Aconiti Radix Cocta and Paeoniae Radix Alba on the transdermal permeation, and provided a reference for studies on the prescription combination regularity and relevant practices.
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Objective: To investigate the effects of common peneration enhancers on the transdermal permeation of total flavones and six flavonoid components from Scutellariae Radix Gel-unguentum (SRGU), thus to provide the experimental evidence for the selection of optimal penetration enhancers. Methods: In vitro diffusion cell method was used to evaluate the changes of the transdermal pemeation parameters by azone (AZ), menthol (MT), and propylene glycol (PG), separately or in combination. Results: When applied individually, AZ and MT showed the best enhancing effect on the transdermal permeability and cumulative permeation of flavonoids and their aglycons, respectively. PG, in contrast, produced poor enhancement. When applied in combination, the permeation enhancing effects were generally more remarkable than those of single enhancer. In particular, 3% AZ + 5% PG could achieve the most effective enhancement effect on the transdermal permeation of flavonoids. Conclusion: Penetration enhancers could significantly affect the transdermal permeation of total flavones and flavonoid components from SRGU in vitro, and 3% AZ + 5% PG may serve as the most effective enhancer.
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Objective: To prepare and optimize the prescription of colchicine ethosomes containing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and to investigate its feasibility as a carrier for transdermal drug delivery. Methods: The colchicine ethosomes containing TPGS were prepared by the injection-sonication method. And the encapsulation efficiency (EE) was determined by minicolumn centrifugation method. The prescription of ethosomes was optimized by uniform design with EE as the evaluation index, and the physicochemical properties of the optimized ethosomes were investigated. Characterization of the vesicles was based on particle size, Zeta potential, entrapment efficiency, and transmission electron microscopy (TEM). The transdermal permeation characteristics of ethosomes, colchicine 30% ethanol solution, and colchicine ethosomes containing TPGS were compared by using Franz diffusion cells. Results: The optimized formulation was as follows: The contents of soybean phospholipid and TPGS were 350 and 50 mg, respectively. In addition, the concentration of ethanol was 36.44%. The average EE, particle size, polydispersity index, and Zeta potential were (74.71 ± 2.18)%, (89.6 ± 3.5) nm, 0.201 ± 0.008, and (-34.6 ± 2.7) mV, respectively. The in vitro experiment showed that the transdermal flux, permeation rate, and skin deposition of colchicine ethosomes were (64.49 ± 5.61) μg/cm2, (2.84 ± 0.23) μg/(cm2∙h), (128.22 ± 11.64) μg/cm2, and the transdermal flux, permeation rate, and skin deposition of colchicine ethosomes containing TPGS were (91.36 ± 7.11) μg/cm2, (4.73 ± 0.38) μg/(cm2∙h), and (182.84 ± 14.37) μg/cm2, respectively, which was significantly higher than those in ethosomes. Conclusion: The colchicine ethosomes containing TPGS show high EE and obviously enhance the percutaneous absorption of colchicine, which might be a potential carrier for transdermal drug delivery.
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OBJECTIVE:To prepare Tacrolimus niosomes (Tac-NS) and evaluate their characteristics in vitro. METHODS:Tac-NS were prepared by a film hydration-ultrasonic method. Using the comprehensive score of encapsulation efficiency (EE%), drug-loading amount,mean particle size and PDI as the evaluation index,orthogonal design was used to optimize the concentration of sorbitan monostearate(Span-60),mole ratio of Span-60 to cholesterol,mole ratio of Span-60 to SDC. The morphology,mean particle size,PDI,Zeta-potential and EE%of Tac-NS were investigated. Accumulative percutaneous penetration(Q)and accumula-tive retention amount(Qs)of Tac-NS and physical mixture of Tac and NS were compared by percutaneous penetration test in vitro. RESULTS:The optimal formulation was as follows as Span-60 0.025 mol/L,mole ratio of Span-60 to cholesterol 10∶1,mole ratio of Span-60 to SDC 15∶1,drug-loading amount of 5%. Tac-NS was spherical and distributed evenly,but hardly congregated.The mean particle size,PDI,Zeta-potential and EE% were (233.0 ± 6.48) nm,0.266 ± 0.021,(-41.7 ± 0.32) mV and (76.83 ± 4.61)%,respectively. The results of in vitro permeability study showed that Qs of Tac-NS was 2.4 times of physical mixture;in ad-dition,Q of the two were similar. CONCLUSIONS:Tac-NS,owning high EE%,small particle size,uniform distribution and ide-al permeation effect,is prepared successfully.
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Objective: To prepare the nanosuspension-based gel of Ganoderma lucidum triterpenoids (GT-NS-gel) and investigate the in vitro transdermal diffusion characteristics. Methods: GT-NS was prepared by high pressure homogenization and then transformed into gel. The formulation of GT-NS-gel was optimized by response surface method with cumulative release of drug from the GT-NS-gel within 24 h, and the amount of drug in the skin after applying GT-NS-gel for 24 h was used as indexes. In vitro percutaneous permeation and skin deposition of GT-NS-gel were studied and compared with those of GT-gel. Results: The GT-NS-gel prepared by optimal formulation (5 mg/g Carbomer 940, 30 mg/g GT, and 47.2 mg/g lecithin) could release in vitro at 24 h to (56.28±2.16)%, and the amount of drug in the skin after applying GT-NS-gel for 24 h was (472.89±8.74) μg/cm2. There was a little deviation between the theoretically predicted value and the measured value. It showed that this model had a good prediction. The amounts of GT penetrating through the skin and in the skin after applying GT-NS-gel for 24 h were (50.73±4.97) and (475.89±10.74) μg/cm2, which were significantly higher than GT-gel (P<0.05). Conclusion: The GT-NS-gel has the ability to increase drug concentration in the skin, which can improve the bioavailability of the local skin.
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carbomer gel(387.93,353.71,220.75,120.93,114.76,and 84.02 ?g?cm-2?h-1,respectively),with liposome and microcapsule showing significantly better percutaneous absorption efficacy than micromulsion and other gels(P
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Objective To study percutaneous absorption kinetics and synergistic penetration enhancement of tetrahydropalmatine,aconitine and ginsenoside Rg1.Methods The in vitro intact and stripped skin permeation experiments were carried out by using Permcell KH-5P horizontal proliferation system.The percutaneous kinetic parameters of tetrahydropalmatine,aconitine and ginsenoside Rg1 were determined by HPLC,and the transdermal behaviors of the three active ingredients and interactions of combination were investigated.Result The cumulative amounts in 24 h of intact skin of tetrahydropalmatine,aconitine and ginsenoside Rg1 were 123.95,50.32,96.25(?10-10 cm2/s).The cumulative amounts in 24 h of stripped skin of them were 539.00,93.60,354.70(?10-10 cm2/s).The LogP were 1.66,0.66 and 0.57 respectively.Each component had cumulated amount permeated of improvement by 64%～293% in coexistence system of three active ingredients.Conclusion The combination of three active ingredients results in a synergistic enhancement effect on percutaneous absorption of every active ingredient,and it is shown that the maximal enhancement effect appears between aconitine and ginsenoside Rg1.
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OBJECTIVE:To establish the Second-order Derivative UV-spectrophotometry for the determination of transdermal osmolality of metoprolol tartrate (MP)in vitro.METHODS:The quantitation of the vibration amplitude (?A)between the characteristic valley and the characteristic peak of MP appeared at 224nm and 234nm in UV-scanning.RESULTS:The linear concentration range of metoprolol tartrate was 5～60?g/ml,the average recovery was 98.89%with average RSD at 2.05%.CONCLUSION:This method can accurately determine the transdermal osmolality of MP in vitro yet without the interference of skin exudates,its operation is simple and fast and the results are accurate and reliable.
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OBJECTIVE: To study the enhancing effect of N-trimethyl chitosan with degree of quaternization of 60% (TMC60) on the estradiol gel in vitro. METHODS: TMC60 was synthesized and the degree of quaternization was determined by 1H-NMR. Three different kinds of estradiol gels, 2% TMC60 group, 2% azone group and blank control group, were studied respectively. The cumulative penetration Q and steady penetration rate J in vitro were used as the indices. The cumulative penetration was calculated. RESULTS: The degree of quaternization of TMC60 was 67.2%. Significant difference was found the value Q and J of TMC60 group when compared to blank control group(P0.05). CONCLUSION: 2% TMC60 is a penetration enhancer with similar enhancing effect as 2% Azone, which deserves further research.