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The purpose of this research was to prepare and evaluate monolithic drug-in-adhesive type patches of Rasagiline Mesylate (RM) containing penetration enhancer and having seven day wear property. Preformulation studies like solubility in permeation enhancers, compatibility study, transmission study, uptake study and crystallization study of Rasagiline Mesylate in various pressure sensitive adhesive polymers were performed. Transdermal system was prepared by solvent casting method. The effects of various permeation enhancers (Propylene Glycol, Oleic Acid, Isopropyl Palmitate, and lauryl lactate) on the ex-vivo transcutaneous absorption of Rasagiline Mesylate through human cadaver skin were evaluated by modified Franz diffusion cell system. Ex-vivo transcutaneous absorption of prepared transdermal patch was performed using different concentration of Lauryl lactate (3%, 5%, and 7%). In-vitro Adhesion testing (Peel, tack shear etc.) was performed on different dry GSM (Grams per Square Meter) of patch like 80GSM, 100 GSM and 150 GSM. The final transdermal patches were tested for appearance, weight of matrix, thickness, % assay of drug content, in-vitro adhesion testing, cold flow study and ex-vivo skin permeation studies. Based on crystallization study and adhesion testing, Durotak-4098 (14% drug concentration) was selected as pressure sensitive adhesive. Patch containing Lauryl lactate showed highest cumulative permeation compared to other permeation enhancers. The patch containing 5% laurel lactate showed greater transdermal flux (2.36 µg/cm2 /hr). Patch with 150 dry GSM showing promising adhesion properties. Backing film Scotchpak 9723 and release liner Saint Gobain 8310 was selected based on transmission and uptake study of Rasagiline Mesylate. Stability study indicates that developed formulation remains stable. In conclusion, the present research confirms the practicability of developing Rasagiline Mesylate transdermal system.
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AIM: To compare the effect of azone and menthol by using the 5-fluorouracil (5-FU) as drug model, and explore the mix effect of the two transdermal enhancers. METHODS: The test acts on the self-made instrument. After the test, calculate the total amount of the drug which has permeate through the skin was calculated and the mixed effect of azone and menthol was estimated by multiple quantity method.RESULTS: Both azone and menthol of concentrations of 0.25%, 0.50%, 1.00% and 2.00% had significant penetration promoting effect on 5-fluorouracil, which were significantly different from the control group (P<0.01). No synergistic effect was detected when evaluating the combined effect of the two drugs by multiple dose method. CONCLUSION: Both azone and menthol have promotion effect on 5-fluorouracil, but the combined use of the two drugs of same concentration show no synergistic effect.
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To investigate the effects of essential oil from three kinds of pungent herbs,namely Menthae Haplocalycis Herba,Atractylodis Rhizoma and Cnidii Fructus,on the transdermal absorption in vitro of alkaloids from Sophorae Flavescentis Radix. The modified vertical Franz diffusion cell was used to conduct a transdermal experiment in vitro with the isolated abdominal skin of the SD rats as the transdermal absorption barrier. The effects of such three kinds of pungent essential oil on percutaneous absorption of alkaloids from Sophorae Flavescentis Radix were investigated by determining the content of 6 alkaloids( oxymatrine,oxysophocarpine,N-methylcytisine,sophoridine,matrine,and sophocarpidine) in the transdermal acceptor with ultra-performance liquid chromatography-triple quadruple mass spectrometry( UPLC-TQ-MS) technique simultaneously. With enhancement ratio( ER) as the index,their effects on promoting penetration was as follows: 1% Atractylodis Rhizoma oil > 1% Cnidii Fructus oil > 3% Azone ≈ 3% Atractylodis Rhizoma oil > 5%Atractylodis Rhizoma oil > 3% Cnidii Fructus oil ≈ 5% Cnidii Fructus oil > 3% Menthae Haplocalycis Herba oil > 5% Menthae Haplocalycis Herba oil > 1% Menthae Haplocalycis Herba oil > Blank. The results showed that these three kinds of pungent essential oil could be used as enhancers for alkaloids of Sophorae Flavescentis Radix,providing scientific guidance for improving percutaneous absorption of alkaloids from Sophorae Flavescentis Radix.
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Animals , Rats , Alkaloids , Metabolism , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal , Metabolism , Oils, Volatile , Pharmacology , Plant Roots , Chemistry , Rats, Sprague-Dawley , Skin Absorption , Sophora , ChemistryABSTRACT
OBJECTIVE: To investigate an efficient hydrating facial mask with olive oil (OL)/vitamin E succinate(VES) as the oil phase(O), and with hyaluronic acid, collagen, sodium alginate, arbutin, allantoin as the active ingredients, using a low concentration of surfactant(S) and alcohol-free microemulsion gel as the carrier. METHODS By investigating the effect of VES and co-surfactant (CoS) propylene glycol on microemulsion region, the microemulsion formulation was screened. The microemulsion characteristics of the facial mask were characterized by transmission electron microscopy and Malvern particle size determination. The moisturizing effect and transdermal absorption capacity of the facial mask were evaluated using a commercially available unifon mask as the reference substance. RESULTS Through the compounding of OL and VES, the microemulsion area of OL was increased, and microemulsion range was largest when the mass ratio of OL to VES was 6∶1.The use of the co-surfactant(propylene glycol) reduced the OL microemulsion area. The microemulsion with O/S mass ratio of 4/6 and water content of 85% was selected as the carrier, and the obtained droplet of the facial mask was round, the average particle size was (58.83±0.79) nm, and the PDI was (0.271±0.001), which were in line with the characteristics of microemulsion. Compared with commercial unifon mask, the moisturizing effect of the self-made microemulsion gel facial mask increased by 20.37%. The steady-state infiltration rates of 1% arbutin from the facial mask through the isolated cavy skin was 0.305 mg•cm-2•h-1, which was 4.29 times higher than that from the marketed unifon mask. This product was safe and stable, and meets the sensory and physicochemical indexes of the national light industry standard QB/T2872-2007. CONCLUSION The facial mask with OL/VES microemulsion gel as the carrier can improve the hydrating effect and the transdermal absorption of the active substance, it is expected to be promoted and developed.
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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 compare in vitro percutaneous permeation characteristics of glycyrrhizic acid in 6 kinds of glycyrrhetate creams,and to provide reference for further development and utilization. METHODS:Modified Franz diffusion cell and isolated rat skin were adopted for in vitro percutaneous permeation test. 24 h accumulative permeation of glycyrrhizic acid in 6 kinds of glycyrrhetate creams(monoammonium glycyrrhizinate,diammonium glycyrrhizinate,monopotassium glycyrrhizinate, dipotassium glycyrrhizate,trisodium glycyrrhizinate,disodium glycyrrhetate)were determined by HPLC. The permeation characteristics of 6 kinds of glycyrrhetate creams were evaluated by calculating percutaneous absorption rate. RESULTS:24 h accumulative permeation of 6 kinds of glycyrrhetate in rat skin in descending order was as follows:trisodium glycyrrhizinate (23.933 μ g/cm2)>dipotassium glycyrrhizinate(22.952 μ g/cm2)>disodium glycyrrhizinate(15.424 μ g/cm2)>monopotassium glycyrrhizinate(10.703 μg/cm2)>diammonium glycyrrhizinate(9.557 μg/cm2)>monoammonium glycyrrhizinate(1.621 μg/cm2). The percutaneous permeation rate in descending order was as follows as trisodium glycyrrhizinate [1.010 2 μ g/(cm2·h)]>dipotassium glycyrrhizinate [0.974 5 μg/(cm2·h)]>disodium glycyrrhizinate [0.641 2 μg/(cm2·h)]>diammonium glycyrrhizinate [0.399 9 μg/(cm2·h)]>monopotassium glycyrrhizinate[0.362 8 μg/(cm2·h)]>monoammonium glycyrrhizinate[0.072 6 μg/(cm2·h)]. CONCLUSIONS:The permeation rate of trisodium glycyrrhizinate is the highest among 6 kinds of glycyrrhetate creams in vitro.
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Objective To establish a method to simultaneously determine syringing and isofraxidin by HPLC;To investigate the features of percutaneous absorption in vitro of Jiegugao blended and pasted by white vinegar, honey and vaseline; To discuss the mechanism of commonly used ointment matrices in Tujia Minority. Methods Rat abdomen skin in vitro was as transdermal barrier;the modified Franz diffusion pool was used to simulate human skin medication; the content of syringin and isoprofen was determined by HPLC; the percutaneous absorption equation was established and the related parameters, such as cumulative permeation rate and permeation rate, were calculated. Results When using Syncronis C18 (250 mm × 4.6 mm, 5 μm) as chromatographic column, acetonitrile-0.1%phosphoric acid as mobile phase, 1.0 mL/min as perfusion speed and 265 nm as determine wavelength, regression equation of syringingwas A=10 686.454 6C+1565.778 8 (r=1.000 0), regression equation of isofraxidin was A=12 297.305 4C-5913.729 9 (r=0.999 9). Cumulative permeation quantity of syringing in Jiegugao blended and pasted by white vinegar, honey, vaseline and blank were 7.549 2, 4.580 3, 3.890 8 and 5.378 4 μg?cm-2?h-1 respectively and permeation rate were 25.66%, 16.11%, 13.73% and 18.78%. Meanwhile, cumulative permeation quantity of isofraxidin were 2.536 9, 1.941 8, 1.178 2 and 2.293 6 μg?cm-2?h-1 respectively and permeation rate were 47.04%, 35.06%, 22.11%and 41.11%. Conclusion Using white vinegar as the ointment matrix can promote the percutaneous absorption of effective composition in Jiegugao blended. However, it will retard the percutaneous absorption of effective composition in Jiegugao when using honey and vaseline as the ointment matrices, but honey and vaseline can be used as a slow-release matrix.
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Objective To optimize the particle size of Huoxue powder by contents comparison of emodin,phellodendrine,berberine and jatrorrhizine before and after permeabilized skin absorption of Huoxue powder in different particle size of 0.150,0.075,0.048,0.038 mm.Methods The contents of emodin,phellodendrine,berberine and jatrorrhizine in transparent absorbent fluid of Huoxue power in different particle size within 24 hours were measured by ultra performance liquid chromatography tandem mass spectrometry,and optimize its particle size by contents comparison of the effective components.Results The contents of the active components in Huoxue power with the particle size of 0.075 mm were high before and after percutaneous absorption.Conclusion Particle size of 0.075 mm is best for Huoxue powder.
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OBJECTIVE: To optimize the formula of celecoxib gel by studying the effects of different doses of penetration enhancers on the penetration of celecoxib through skin in vitro. METHODS: With sodium alginate as the gel base, factorial design method was used to choose the optimal formula of penetration enhancers among four different formulas to prepare celecoxib gels. The release rate of celecoxib in the release media was detected by modified Franz diffusion cells method, and the steady percutaneous speed (J), permeability coefficient (Kp) and the accumulative permeation quantity (Q) in 12 h were calculated. RESULTS: The accumulative permeation quantity (Q) in 12 h of celecoxib from the gels made with the four different formulas were 27.93, 25.12, 18.79 and 19.35 μg·cm-2, respectively. The gel with 1% azone and 1% menthol as penetration enhancers had the maximum Q value, 27.93 μg· cm-2, its penetration process conformed to Higuchi equation, and the steady percutaneous speed (J) and permeability coefficient(Kp) were also higher than the other three experimental groups. CONCLUSION: With sodium alginate as the gel base, azone and menthol have a synergistic effect on the percutaneous penetration of celecoxib gels, and the best formula is 1% azone and 1% menthol.
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Objective To investigate the effects of different penetration enhancers on percutaneous absorption of Xiaoyan Runma mucilage in vitro, and to improve the curative efficacy of this mucilages through selection of the effective penetration enhancers. Methods Xiaoyan Runma mucilage was prepared with different penetration enhancers. An intelligent permeability instrument was used for in vitro percutaneous absorption test of rats , with isolated mice abdomen skin serving as in vitro transdermal barrier and saline isotonic solution as receptor fluid. Then the contents of lidocaine hydrochloride in receptors were determined by HPLC.The accumulative transit dose (Q) and percutaneous permeability (J) within 12 h were calculated and compared with those of mucilage without any enhancer. Results With Q value serving as an index, different enhancers had different promote permeation effects on Xiaoyan Runma mucilage, and the effects in descending order were as follows:4% azone [(222.75±3.4) μg?(cm2)-1]>2% azone[(207.42±5.1) μg?(cm2)-1]>3% menthol [(183.38±4.9) μg?(cm2)-1]>5%menthol [(160.82±5.4) μg?(cm2)-1]>2% azone+3% menthol [(151.25±5.5) μg?(cm2)-1]>2% azone+5% isopropyl myristate [(127.26±7.1) μg?(cm2)-1]>2% oleic acid [(125.16±6.5) μg?(cm2)-1]>no enhancer [(109.82±8.2)μg?(cm2)-1].4% azone was the best penetration enhancer for the mucilage delivery in vitro, with Q and J value as [(222.75± 3.4)μg?( cm2 )-1 ] and 19. 896 μg?( cm2 )-1?h-1 , respectively, which was 2. 08 times those of mucilages without any enhancer. Conclusion Being as a transdermal absorption enhancer of Xiaoyan Runma mucilage, 4% azone has the best effect. This study can provide the optimal formulation for transdermal delivery system of Xiaoyan Runma mucilage.
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OBJECTIVE:To study the percutaneous absorption of 0.03% Tacrolimus ointment,and to compare the difference of domestic test preparation and imported reference preparation. METHODS:Modified Franz diffusion cells were adopted in trans-dermal test in vitro;HPLC-MS method was used to determine permeation amount and rate in vitro,delay time of domestic test preparation and imported reference preparation 0.03%Tacrolimus ointment. RESULTS:24 h in vitro permeation amount of test and reference preparations were(3 907±1 191)and(3 896±1 064)ng/cm2;permeation rates were 186.7 and 182.9 ng/(cm2·h);de-lay time were 1.95 and 2.00 h,respectively(P>0.05). CONCLUSIONS:Test preparation shows good percutaneous property,and is similar to reference preparation in penetration absorbency through nude mice skin.
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Transdermal drug delivery is an administration route which can avoid the first-pass effect,maintain steady plasma concentrations and enhance bioavailability. Drug transporting through the skin by passage through the stratum corneum leads to the viable epidermis and the dermis.With the development of the computer technology,many mathematical models for predic-ting the absorption of drugs have been built according to physical and chemical properties of drugs and physiological characteristics of each skin layer.This article presented provides a summary of the progress of mathematical models for predicting percutaneous absorption of drugs.
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Application of penetration enhancers (PE) is one of the most commonly used strategies to improve the percutaneous absorption. Most essential oils from Chinese materia medica (CMM) possess the good ability to enhance percutaneous absorption, minor skin irritation, and certain therapeutic efficacy. Therefore, the research on essential oils as PE has good prospects. In the present paper, the percutaneous absorption enhancing effects, mechanism of action, safety, and transdermal absorption of essential oils from CMM are reviewed. Moreover, the existing main problems, namely the confusing application of pharmaceutical preparations and the limitation of in vitro percutaneous absorption evaluations, are summarized and analyzed. Then the research ideas are proposed on the basis of the analysis results. The application scope, dosage forms, and mechanism of action of essential oils from CMM as PE should be further studied and standardized. More attention should be paid to the guiding role of CMM theory.
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Objective: To evaluate the in vitro percutaneous absorption profiles of ginsenoside Rh1 using ionic liquids [BMIM][Cl] as a novel permeation enhancer and to investigate the mechanism. Methods: Mice skin and porcine skin were used as skin model. Oil acid, isopropyl myristate, and menthol were used as comparing skin enhancers. The solubility of Rh1 (with or without enhancer) in water was measured by shake-flask method. Skin permeation experiment was performed using Franz diffusion cells. Skin structure change after treatment of [BMIM][Cl] was measured by FTIR. Results: By comparing with commonly used enhancers, 5% [BMIM][Cl] significantly increased the solubility of Rh1 and gave an excellent improvement on the skin penetrability of Rh1. The FTIR results suggested that [BMIM][Cl] accelerated the drug skin permeation by disrupting the lipid bilayer of skin stratum corneum. Conclusion: [BMIM][Cl] can serve as a novel skin permeation enhancer, and show a broad application prospect in transdermal drug delivery system.
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The term percutaneous absorption covers the entire process by which a drug applied to the outer surface of the skin is taken up into the systemic circulation. This requires penetration into the layers of the skin with subsequent permeation across each layer and finally uptake into the capillary blood vessels in the upper region of the dermis. It is necessary to consider both the structure of the membrane and the interactions of the three components – membrane, penetrant and vehicle to determine the physical and chemical factors which assist or hinder the process. Not all drug substances are suitable for transdermal delivery. Among the factors playing a part in percutaneous absorption are the physical and chemical properties of the drug, including its molecular weight, solubility, partition coefficient, dissociation constant (pKa), the nature of the carrier vehicle, and the condition of the skin. Although general statements applicable to all possible combinations of drug, vehicle, and skin condition are difficult to draw, most research findings were tried to summarize in this review article.
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Transdermal applications of drugs present many advantages in terms of absorption, however this is not easily obtained through the transdermal route. The principle barrier is the stratum corneum and one of the strategies that have been found to promote cutaneous drug penetration is through the use of absorption enhancers. Many substances have been identified as absorption enhancers. Although the list of substances that promote absorption is growing, in most cases, there is a direct correlation between the effects of absorption enhancers and their skin toxicity. The use of these substances depends therefore on studies which focus on local and systemic toxicity, as well as action mechanisms.
A via transdérmica para a absorção de fármacos apresenta várias vantagens, porém a absorção através desta via não é fácil de ser obtida. A principal barreira encontrada é o estrato córneo e uma das estratégias encontradas para promover a permeação cutânea de fármacos é o uso de promotores de absorção. Há uma variedade de substâncias identificadas como promotores de absorção. Enquanto a lista de substâncias de promotores de absorção percutânea vem aumentando, na maioria dos casos, há uma correlação entre o efeito promotor e a toxicidade para a pele. O emprego destas substâncias depende, portanto, de estudos enfocando a toxicidade local e sistêmica, bem como o mecanismo de ação.
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Absorption , Administration, Cutaneous , Pharmaceutical PreparationsABSTRACT
glycerol,and the best penetrable concentrations for it were 0.5%,0.5% and 0.2%,respectively.No obvious penetration efficacy was noted for glycerol.CONCLUSIONS: 4 kinds of penetrations enhances can increase the percutaneous absorption of DH under the certain concentration.
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IPA.Skin permeation was significantly enhanced by increasing the loading concentration of OA or NMP,larger IPA amount(8%) or PG amount(20%) could inhibit the permeation of artesunate.Conclusion Oleic acid was found to be the most efficient enhancer for artesunate,10% is the most effective concentration.
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OBJECTIVE:To study the determination method of the percutaneous rate of Kechuan xuewei patch and its in vitro drug release profile.METHODS:The content of ephedrine hydrochloride(an index composition)in percutaneous reception fluid and release fluid were determined by HPLC,and the percutaneous penetration rate and the in vitro drug release rate were computed.RESULT:Ephedrine permeated at a constant rate of 6.467 9 ?g?cm-2?h-1/2 and the in vitro drug release rate was 21.382 ?g?cm-2?h-1/2,fitting Higuchi equation.CONCLUSION:Kechuan xuewei patch can be prepared as controlled release matrix system of skin permeation rate-limited type.
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BACKGROUND: Packs are viscous preparations that produce a film over the skin surface, thus preventing the evaporation of water and increasing the skin temperature. Because of this occlusive effect, packs can be used as the vehicle to which active pharmacologic agents produce a therapeutic effect. OBJECTIVE: This study aimed to explore the feasibility of pack formulation as a vehicle by comparing percutaneous absorption with ointment formulation. METHODS: After 0.5, 1, 2 and 6 hours of topical applications of 0.05% clobetasol 17-propionate ointment and pack on each forearm of 9 young, healthy male subjects, the amounts of the drug in tape-stripped stratum corneum were assessed using high performance liquid chromatography(HPLC). RESULTS: There was no significant difference with regard to the amount of the drug in tape-stripped stratum corneum between ointment and pack formulations of 0.05% clobetasol 17-propionate. CONCLUSION: Pack formulations delivered similar amount of drugs to the skin compared to ointment formulations, suggesting peel-off type pack can be used as a new vehicle of topical corticosteroids.