Preparation Method of Pavarerine Hydrochloride Lecithin Microemulsion and the Research on Its Transdermal Absorption
|School||Southern Medical University,|
|Keywords||Transdermal drug delivery Microemulsion PAPAVERINE Steady-state flow in vitro|
Background: flap part or all of necrosis, which is a surgical flap or tissue to repair the most common problems. Flap necrosis pathological mechanism involving many factors, clinical flap pathophysiology changes in the process of clinical adopted a series of systemic and local processing to improve the survival rate of the flap. Systemic variety of vasodilators, anticoagulants, anti-leukocyte adhesion drugs, and adrenal corticosteroids and the prevention and treatment of skin flap ischemia, but systemic side effects or ineffective unable to extensive use in clinical practice. Study attempts to the local use in the flaps a transdermal absorption preparation containing these drugs in order to avoid systemic side effects, and improve efficacy. Consider the topical application of drugs (transdermal drug delivery) is a very effective method, there are a variety of transdermal drug delivery formulations can improve flap blood supply. The anticoagulant effect of heparin may improve the flaps vascular patency rate, local direct input of low-dose heparin (dose not affect the systemic coagulation and systemic coagulation status changes), to reduce the risk of bleeding and hematoma flap, increased flap tolerance to the ability of primary venous congestion. The studies have confirmed that: the small molecules more easily in the case of the hydration of the stratum corneum through the skin tissue, the same mechanism of action and efficacy of the low molecular weight heparin and heparin. Experiments show nanoliposome nasal absorption of low molecular weight heparin good role in promoting. The prostaglandin E 1 sub of (PGE , 1 ), dilate blood vessels and anti-platelet aggregation, reduce the generation of oxygen free radicals. Researchers will contain different PGE concentration of rapid transdermal absorbent 1 topical cream applied in animal ischemic flap surface, compare the effect of each application, based on observing the typical clinical cases to trial drug efficacy, found human arterial smooth muscle content is much larger than the vein. Papaverine (pavarerine hydrochloride) smooth muscle has a relaxant effect of the blood vessels, gastrointestinal tract, bile duct, the prevention flap ischemia conventional intravenous route using vasodilator papaverine hydrochloride, but the large amount of short treatment interval, resulting in toxic side effects . Early someone will papaverine made topical formulations for the treatment of impotence. In recent years, Some experimental studies have shown that papaverine gel and papaverine cream can percutaneous absorption, and can speed up the rate of expansion, improve skin blood circulation, improve the survival rate of expansion flap. Rely mainly on drug percutaneous absorption drug concentration gradient and the electrochemical gradient penetration. Drugs through the stratum corneum, epidermis and dermal penetration process, the stratum corneum and epidermis is the rate-limiting key parts; However, the flap avulsion flap cycle with normal skin, drug transdermal absorption mechanism and efficiency may be different, how to improve the efficiency of drug penetration is the focus of the study. Methods to enhance the efficiency of drug penetration pharmaceutical, physical, and chemical methods, but different drugs for different pro-penetration method. Currently, transdermal drug delivery system using microemulsion become a research focus, and more and more people pay attention. Microemulsion droplets is generally mediated 10-100nm, small particle size, as a transdermal carrier, to increase the solubility of the lipophilic or hydrophilic drugs, to enhance the rate of transdermal drug to maintain a constant effective blood concentration and improve bioavailability, stability, and rapidly absorbed completely, can enhance the efficacy and reduced toxicity, its oral, injectable, nasal, through the microporous membrane can disinfection sterilization and other advantages. Transdermal mechanisms: microemulsion on the lipophilic or hydrophilic drugs have a higher solubility, after administration to produce a higher concentration gradient; role of some of the components in the microemulsion has a penetration enhancers; oil phase The type and amount can change the affinity of the drug, is conducive to the drug into the stratum corneum. The development of particle size than creams, gels and penetration compared with its strong PAPAVERINE - lecithin microemulsion and investigate its transdermal ability, in order to provide a basis for clinical studies. Purposes: 1. Microemulsion pseudo-ternary phase diagrams investigated microemulsion formation of the size of the area to choose the basic system to meet the the medicinal the microemulsion requirements of microemulsion; investigated by orthogonal design PAPAVERINE - the lecithin microemulsion formulation of influencing factors inspection in order to optimize the prescription; microemulsion maximum drug loading and stability. Papaverine hydrochloride-containing microemulsion by contrast, a suspension, an aqueous solution of transdermal ability to detect the papaverine hydrochloride - lecithin microemulsion transdermal performance and causes; established HPLC detection method to determine the hydrochloride poppy The alkali - the lecithin microemulsion and penetration skin the permeate PAPAVERINE after content. Method: 1. Establish the content of PAPAVERINE detection method: HPLC method with UV detector. The preparation of the standard solutions of papaverine hydrochloride, the establishment of standard curve equation, papaverine hydrochloride - lecithin microemulsion and in vitro permeate papaverine hydrochloride peak area was measured to calculate the measured amount. Chromatographic conditions: chromatograph column: C18 column (250mm × 4.6mm, 5um, Lanzhou); mobile phase: methanol - water - triethylamine (60:40:0.001) (v: v: w); flow rate: 1.0ml · min -1 sup>, detection wavelength: 248nm, temperature: room temperature. 2 lecithin microemulsion Preparation: Filter ① basic system: The pseudo-ternary phase diagrams first determine Km (Km = help surface active agent / surfactant paper with AS on behalf of surfactant and cosurfactant mixed system O represents the oil phase, W represents the water, M represents a microemulsion region.), and then with an oil phase to a different proportion (AS / 0 = 9:1,8:2,7:3 .... 1:9) mixed placed in the test tube with stopper, water was added dropwise, and the changes observed in a test tube, and the refining zone as a single phase microemulsion region. The influence of different surface-active agent, a cosurfactant, an oil phase, and Km values ??microemulsion formed to determine the basic architecture of the microemulsion. (2) optimize the prescription, select Km, the amount of surfactant and water relative to the amount of three factors: filtered microemulsion system based on three concentration levels, orthogonal design prescriptions examine various factors microemulsion viscosity, particle size conductivity, refractive index and in vitro transdermal steady-state flow, select a small particle size, drug loading, in vitro transdermal steady-state flow is the best prescription. ③ Solubility detection: isopropyl myristate, ethanol, lecithin, and blank microemulsion (prescription), pure water as a solvent, the same volume of solvent added in excess papaverine hydrochloride, placed with stopper ampules. Ultrasound drug no longer dissolved, then add the oscillator, shaking at 37 ℃ for 24 h. The saturated PAPAVERINE solution to 3 000 r / min speed centrifugal 10min supernatant clear solution was diluted with methanol using 0.22μm inorganic membranes or organic membrane filter, take 10μl direct injection. By HPLC determination PAPAVERINE content. ④ stability testing: best prescription prepared batches of microemulsion after microemulsion encapsulated in a 10ml vial with stopper, sealed, at room temperature to stand at room temperature, according to the 2005 Pharmacopoeia in 0,1 , February and March, June, the sample was removed, inspect the project, including the particle size, the color of the solution containing the dose was diluted with methanol to the linear range, respectively, sample concentration peak area (n = 5). . Prepared according to the results of the pseudo-ternary phase diagrams and orthogonal design to choose the best prescription drug-containing microemulsion, add water to destroy its structure, so turbid. Preparing a drug-containing aqueous solution containing drug. Three drug content 20mg, examine the steady-state flow and time delay, draw a cumulative release curve. Results: 1. Papaverine hydrochloride in 0.1812 ~~ of .6040 ug.ml -1 sup> sup> concentration range of injection volume and peak area showed a good linear relationship (r = 0.9999): respectively the different prescription volume (80%, 100%, 120%) PAPAVERINE recovery rate was 97.94%, 99.46%, 98.12%, and the average recovery rate was 98.51%; RSD were 0.44%, 0.4%, 0.50%, and the average RSD 0.82% (n = 5). The drug retention time of 9 ~ 10min, microemulsion and in vitro permeate excipients on the content of the sample is measured without interference. Experimental procedure found in isopropanol and n-butanol as a cosurfactant, the formation of the viscosity of the microemulsion region is relatively large, the gel generated; peanut oil and soybean salad no microemulsion region appears to ten four-isopropyl oil phase is larger microemulsion region; the microemulsion area of ??not with the Km of the increase in direct proportion to the increase. Therefore, in line with the requirements of the Pharmaceutical Microemulsions system consisting of isopropyl myristate / lecithin / ethanol / water, consistent with the literature. Smaller particle size when the water phase / oil phase / Km [lecithin / ethanol (1:1)] (w: w: w) microemulsion 10:20:70 steady flow, containing a larger amount of drugs. According to the solubility should be prepared blank microemulsion, after adding the drug raw materials to obtain the maximum drug loading. Papaverine hydrochloride - the lecithin microemulsion placed 6 months, preparations stability. Papaverine hydrochloride - lecithin microemulsion, suspension and aqueous solution in vitro transdermal experimental results for one-way variance analysis, the three transdermal steady-state flow were significantly different (p <0.05), transdermal Delay no significant difference (p> 0.05). The steady-state flow minimum microemulsion, aqueous solution. Transdermal reasons related to its stable structure. Conclusion: This product prescriptions more reasonable, the preparation process is relatively simple, in vitro tests have the obvious effect of penetration. 2 established by the detection method are applicable to papaverine hydrochloride - the lecithin microemulsion and in vitro permeate papaverine hydrochloride content of determination.