Ionic liquids as the effective technology for enhancing transdermal drug delivery: Design principles, roles, mechanisms, and future challenges.

Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs; as novel solvents for improving the solubility of drugs in carriers; as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs; and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structure-activity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs.

M1 Macrophage-Biomimetic Targeted Nanoparticles Containing Oxygen Self-Supplied Enzyme for Enhancing the Chemotherapy.

Tumor hypoxia is considered one of the key causes of the ineffectiveness of various strategies for cancer treatment, and the non-specific effects of chemotherapy drugs on tumor treatment often lead to systemic toxicity. Thus, we designed M1 macrophage-biomimetic-targeted nanoparticles (DOX/CAT@PLGA-M1) which contain oxygen self-supplied enzyme (catalase, CAT) and chemo-therapeutic drug (doxorubicin, DOX). The particle size of DOX/CAT@PLGA-M1 was 202.32 ± 2.27 nm (PDI < 0.3). DOX/CAT@PLGA-M1 exhibited a characteristic core-shell bilayer membrane structure. The CAT activity of DOX/CAT@PLGA-M1 was 1000 (U/mL), which indicated that the formation of NPs did not significantly affect its enzymatic activity. And in vitro drug release showed that the cumulative release rate of DOX/CAT@PLGA-M1 was enhanced from 26.93% to 50.10% in the release medium of hydrogen peroxide, which was attributed to the reaction of CAT in the NPs. DOX/CAT@PLGA-M1 displayed a significantly higher uptake in 4T1 cells, because VCAM-1 in tumor cells interacted with specific integrin (α4 and ß1), and thereby achieved tumor sites. And the tumor volume of the DOX/CAT@PLGA-M1 group was significantly reduced (0.22 cm3), which further proved the active targeting effect of the M1 macrophage membrane. Above all, a novel multifunctional nano-therapy was developed which improved tumor hypoxia and obtained tumor targeting activity.

Design of Dual-Targeted pH-Sensitive Hybrid Polymer Micelles for Breast Cancer Treatment: Three Birds with One Stone.

Breast cancer has a high prevalence in the world and creates a substantial socio-economic impact. Polymer micelles used as nano-sized polymer therapeutics have shown great advantages in treating breast cancer. Here, we aim to develop a dual-targeted pH-sensitive hybrid polymer (HPPF) micelles for improving the stability, controlled-release ability and targeting ability of the breast cancer treatment options. The HPPF micelles were constructed using the hyaluronic acid modified polyhistidine (HA-PHis) and folic acid modified Plannick (PF127-FA), which were characterized via 1H NMR. The optimized mixing ratio (HA-PHis:PF127-FA) was 8:2 according to the change of particle size and zeta potential. The stability of HPPF micelles were enhanced with the higher zeta potential and lower critical micelle concentration compared with HA-PHis and PF127-FA. The drug release percents significantly increased from 45% to 90% with the decrease in pH, which illustrated that HPPF micelles were pH-sensitive owing to the protonation of PHis. The cytotoxicity, in vitro cellular uptake and in vivo fluorescence imaging experiments showed that HPPF micelles had the highest targeting ability utilizing FA and HA, compared with HA-PHis and PF127-FA. Thus, this study constructs an innovative nano-scaled drug delivery system, which provides a new strategy for the treatment of breast cancer.

Mechanistic Study of Release Characteristics of Two Active Ingredients in Transdermal Patch Containing Lidocaine-Flurbiprofen Ionic Liquid.

Ionic liquids (ILs) have been proven to be an efficient technology for enhancing drug skin permeability. However, the question of whether the two components of ILs are released synchronously in transdermal preparations has remained unclear. Thus, this study aimed to investigate the release characteristics of two components of ILs and their underlying molecular mechanism. The ILs containing flurbiprofen (FLU) and lidocaine (LID) were synthesized and characterized. The four typical acrylates pressure sensitive adhesives (PSAs) with different functional groups were synthesized and characterized. The effects of PSAs on the release characteristics of two components of ILs were investigated by drug release tests and verified by skin permeation experiments. The action mechanisms were revealed by FTIR, Raman, dielectric spectrum, and molecular docking. The results showed that the average release amount of FLU (0.29 µmol/cm2) and LID (0.11 µmol/cm2) of ILs in the four PSAs was significantly different (p < 0.05), which illustrated that the two components did not release synchronously. The PSA−none and PSA−OH with low permittivity (7.37, 9.82) interacted with drugs mainly by dipole-dipole interactions and hydrogen bonds. The PSA−COOH and PSA−CONH2 with high permittivity (11.19, 15.32) interacted with drugs mainly by ionic bonds and ionic hydrogen bonds. Thus, this study provides scientific guidance for the application of ILs in transdermal preparations.

Effect of the combination of permeation enhancer and ion-pairs strategies on transdermal delivery of tofacitinib.

The aim of the present study was to develop a tofacitinib (TOF) transdermal patch by the combination of ion-pairs and chemical permeation enhancer strategies. And a theory of controlled release of chemical permeation enhancers by counterion was proposed on the basis of in vitro skin permeation and skin retention study. Through the in vitro skin permeation study, the formulation factors such as counterion, pressure sensitive adhesive (PSA), drug loading and patch thickness were investigated, and the optimized patch (6.5% LA-TOF, 15% POCC and thickness = 50 µm) was evaluated by the pharmacokinetic study. The AUC0-t of the optimized patch was 529.89 ± 45 h ng/mL. Special attention has been paid to the molecular mechanism of the effects of counterion concentration on the release and permeation enhancement effect of penetration enhancer. FTIR study, 13C NMR, XPS and molecular modeling were conducted to investigate the molecular interaction between POCC and LA. Raman Imaging and ATR-FTIR were used to explore the POCC content in the skin and the interference degree to lipid. The results revealed that a strong hydrogen bond appeared between LA and the hydroxyl group of POCC, which inhibited the release of POCC, thus reducing the lipid disturbance and permeation enhancement effect of POCC. In conclusion, this TOF patch was successfully developed. The effect of counterion on permeation enhancers was clarified at molecular level, and these results provided references for the development of TOF patch.

An investigation on the effect of drug physicochemical properties on the enhancement strength of enhancer: The role of drug-skin-enhancer interactions.

The aim of present work was to investigate the influence of drug physicochemical properties on the enhancement effect of enhancers, which guided the application of enhancers in different drug transdermal prescriptions. Firstly, Polyglyceryl-3 dioleate (POCC) was selected as a model enhancer and its enhancement effect on ten drugs was assessed by in vitro skin permeation experiment. Secondly, the correlation analysis of physicochemical properties of drugs was carried out from the aspects of partition and permeation. The interactions of drug-skin-POCC were elucidated by FT-IR, molecular docking, solubility parameters calculation, ATR-FTIR, Raman study, molecular dynamics simulation and confocal laser scanning microscopy (CLSM). The results showed that the enhancement ratio (ER) of drugs was ranging from 2.23 to 7.45. On one hand, the miscibility between drugs with low polar surface area (P.S.A) and donor solution was decreased more pronounced by the addition of POCC because of the drug was difficult to form hydrogen-bond with POCC, facilitating the vehicle/SC partition of drugs. On the other hand, the permeation of drugs with low P.S.A and polarizability was enhanced more significantly by POCC because the drug was less likely to interact with skin lipids compared to others, causing that POCC had more chance to interact with skin lipids to improve permeation drugs across the SC more easily. In conclusion, the different strength of drug-skin-POCC interactions was the main reason for the discrepancy in the enhancement effect of the POCC on ten drugs, which laid a basis for the research on the drug-specific molecular mechanisms of enhancers.

The molecular design of drug-ionic liquids for transdermal drug delivery: Mechanistic study of counterions structure on complex formation and skin permeation.

Though ionic liquids (ILs) as novel enhancers had garnered wide attention, detailed studies elucidating molecular design of drug-ILs were missing and mechanisms of their formation and skin permeation were still lacking. Herein, we systematically investigated effects of counterions structures on formation and skin permeation of drug-ILs. Firstly, effects of counterions on formation of drug-ILs were dependent on polarizability, molecular weight (M.W.) and polar surface area of counterions. It was caused by strong charge assisted hydrogen bond and van der Waals interactions revealed through FT-IR, X-ray photoelectron spectroscopy and molecular docking, which undermined ionic interactions and reduced total interaction strength, thereby produced lower lattice energy. Then, skin permeability of drug-ILs had a good parabola relationship with M.W., polarizability and log P of counterions. The underlying mechanism was the increased drug miscibility with stratum corneum, which caused conformational disorder and phase transition of lipid bilayers characterized by ATR-FTIR, DSC and confocal laser scanning microscopy. Finally, the drug-ILs proved to be non-irritating using in vivo skin erythema analysis. In conclusion, the quantitative structure-activity relationship models based on counterions structure to predict formation and skin permeation of drug-ILs were developed, which provided basic theory for design of drug-ILs with high permeation-enhancing efficiency.

An investigation on percutaneous permeation of flurbiprofen enantiomers: The role of molecular interaction between drug and skin components.

This work aimed to investigate skin permeation profiles of chiral flurbiprofen and clarify the molecular mechanism of transdermal permeation difference of enantiomers. The in vitro transdermal permeation of enantiomers through rat skin was studied by diffusion cells. Physicochemical parameters of model chiral drugs were determined. Molecular interaction between chiral flurbiprofen and ceramides of skin was investigated by FTIR, 13C NMR and molecular docking. The skin permeation mechanism of chiral drugs was characterized by ATR-FTIR, Raman spectra, DSC and molecular dynamic simulation. The results showed that the amount of the permeation and retention amount of (S)-flurbiprofen was 1.5 times over that of (R)-flurbiprofen. And it was proven that the difference was not induced by physicochemical properties but the molecular interaction between drug-skin components. (S)-flurbiprofen was easy to form stronger hydrogen bonding with -CONH group of skin lipids due to its steric configuration, which disturbed lipids arrangement more easily according to the results of ATR-FTIR (ΔνasCH2 = 1.00 cm-1), Raman spectra (ΔI2882/I2853 = 0.32) and the DSC (ΔTm stratum corneum = 11.75 °C). It was demonstrated more obvious effect on the second structure of keratin by ATR-FTIR study (Δ Amide I = 3.60 cm-1 and Δ Amide II = 3.38 cm-1). Better compatibility between (S)-flurbiprofen and lipids was confirmed quantificationally by thermodynamic analysis. In conclusion, the higher interaction between (S)-flurbiprofen and skin components, the higher skin permeation, which contributes to decrease the administration dose and increase the therapeutic effect.

Mechanism insight on drug skin delivery from polyurethane hydrogels: Roles of molecular mobility and intermolecular interaction.

Though polyurethane (PU) hydrogel had great potential in topical drug delivery system, drug skin delivery behavior from hydrogel and the underlying molecular mechanism were still unclear. In this study, PU and Carbomer (CP as control) hydrogels were prepared with lidocaine (LID) and ofloxacin (OFX) as model drugs. In vitro skin permeation and tissue distribution study were conducted to evaluate the drug delivery behaviors. The underlying molecular mechanisms were characterized by drug release with octanol as release medium, rheological study, ATR-FTIR, NMR, and molecular simulation. The results showed that the skin permeation amount of LID-PU (45.50 ± 7.12 µg) was lower than LID-CP (45.50 ± 7.12 µg). And the LID diffusion coefficient of PU (26.21 µg/h0.5) was also lower than CP (31.30 µg/h0.5), which attributed to H-bonding between LID (-CONH) and PU (-NHCOO). However, the OFX-PU showed a higher skin permeation amount (10.06 ± 1.29 µg) than OFX-CP (5.28 ± 1.39 µg). And the OFX-PU also showed a higher diffusion coefficient (30.0 µg/h0.5) than OFX-CP (21.37 µg/h0.5), which was caused by increased mobility of hydrogel when interaction action site was C-O-C in PU. In conclusion, drug skin delivery behavior from PU hydrogel was controlled by molecular mobility and intermolecular interaction, which clarified the influence of the functional group of PU hydrogel on drug skin delivery behavior and broadened our understanding of PU hydrogel application in topical drug delivery system.

Enhanced Drug Loading in the Drug-in-Adhesive Transdermal Patch Utilizing a Drug-Ionic Liquid Strategy: Insight into the Role of Ionic Hydrogen Bonding.

Though pharmaceutical polymers were widely used in inhibiting drug recrystallization via strong intermolecular hydrogen and ionic bonds, the improved drug stability was achieved at the cost of the drug release rate or amount in the drug-in-adhesive transdermal patch. To overcame the difficulty, this study aimed to increase drug loading utilizing a novel drug-ionic liquid (drug-IL) strategy and illustrate the underlying molecular mechanism. Here, naproxen (NPX) and triamylamine (TAA) were chosen as the model drug and corresponding counterion, respectively. In addiiton, carboxylic pressure-sensitive adhesive (PSA) was chosen as the model polymer. The drug-IL (NPX-TAA) was synthesized and characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and proton nuclear magnetic resonance. The miscibility between NPX-TAA and PSA was assessed using microscopy study, X-ray diffraction, fluorescence spectroscopy, and solubility parameter calculation. In addition, molecular mechanisms of crystallization inhibition were revealed by FT-IR, Raman spectroscopy, DSC, X-ray photoelectron spectroscopy (XPS), and molecular docking. Finally, the release pattern of the high load patch of NPX-TAA was evaluated using in vitro drug release and verified by a skin permeation experiment. The results showed that drug loading in PSA was increased by 5.0 times, which was caused by the synergistic effect of strong ionic hydrogen bonding (the decreased intensity and blue shift of the O-H peak of COOH in PSA) formed between NPX-TAA and PSA-COO- and normal hydrogen bonding (red shift of the C═O peak in PSA) formed between NPX-TAA and the carbonyl group of PSA. In addition, -NH+ of TAA was confirmed as the molecular basis of ionic hydrogen bonding through new peak appearance (binding energy: 400.0 eV) in XPS spectra. Moreover, high drug release percent (80.8 ± 1.8%) was achieved even at high drug loading compared with the control group (72.4 ± 2.2%). Thus, this study introduced an effective drug-IL method to enhance drug loading capacity and illustrated the brand-new action mechanism, which provided a powerful instrument for the development of a high drug loading-high release patch.

Mechanistic insights of the controlled release capacity of polar functional group in transdermal drug delivery system: the relationship of hydrogen bonding strength and controlled release capacity.

BACKGROUND: Hydrogen bonding interaction was considered to play a critical role in controlling drug release from transdermal patch. However, the quantitative evaluation of hydrogen bonding strength between drug and polar functional group was rarely reported, and the relationship between hydrogen bonding strength and controlled release capacity of pressure sensitive adhesive (PSA) was not well understood. The present study shed light on this relationship. METHODS: Acrylate PSAs with amide group were synthesized by a free radical-initiated solution polymerization. Six drugs, i.e., etodolac, ketoprofen, gemfibrozil, zolmitriptan, propranolol and lidocaine, were selected as model drugs. In vitro drug release and skin permeation experiments and in vivo pharmacokinetic experiment were performed. Partial correlation analysis, fourier-transform infrared spectroscopy and molecular simulation were conducted to provide molecular details of drug-PSA interactions. Mechanical test, rheology study, and modulated differential scanning calorimetry study were performed to scrutinize the free volume and molecular mobility of PSAs. RESULTS: Release rate of all six drugs from amide PSAs decreased with the increase of amide group concentrations; however, only zolmitriptan and propranolol showed decreased skin permeation rate. It was found that drug release was controlled by amide group through hydrogen bonding, and controlled release extent was positively correlated with hydrogen bonding strength. CONCLUSION: From these results, we concluded that drugs with strong hydrogen bond forming ability and high skin permeation were suitable to use amide PSAs to regulate their release rate from patch.

Molecular mechanism of high capacity-high release transdermal drug delivery patch with carboxyl acrylate polymer: Roles of ion-ion repulsion and hydrogen bond.

In this study, a high capacity-high release transdermal patch was conducted with COOH polyacrylate polymer (PA-1) and non-steroidal anti-inflammatory drugs (NSAIDs), which were characterized using miscibility study, in vitro drug release, drug skin absorption studies in vitro and in vivo. And ibuprofen with the highest cargo loading capacity was chosen as a model drug to investigate innovative molecular mechanism, which was proposed based on ion-ion repulsion and hydrogen bond by FT-IR, Raman, 13C NMR and X-ray photoelectron spectroscopy (XPS). Drug loading and skin absorption in PA-1 was improved up to 2.4 and 2.5 times, respectively. The hydrogen bond formed between drug (COOH) and PA-1 (COOH) was weaken by repulsive interaction using FT-IR and Raman spectra, and molecular mobility of PA-1 was elevated by dielectric spectroscopy. And COO- was confirmed as molecular basis of repulsion in PA-1 through new peak appearance (α-carbon of COOH: 77.22 ppm) of 13C NMR and 9% increased carbonyl content in XPS spectra. It was further confirmed by enhanced conductivity of PA-1 with dielectric spectroscopy, EPR spectra, four-point probe method and molecular modeling by appearance of COO-. In conclusion, our results revealed that ion-ion repulsion decreased hydrogen bonding to construct a high capacity-high release patch.

A systematic approach to determination of permeation enhancer action efficacy and sites: Molecular mechanism investigated by quantitative structure-activity relationship.

The present study was to systematically evaluate the enhancement action efficacy and sites of chemical permeation enhancer (CPEs), which provided references for the reasonable application of CPEs and the formula optimization of transdermal patch. Enhancement action efficacy was characterized using an indicator of comprehensive enhancement effect (ERcom). In addition, enhancement action sites were evaluated using a novel enhancement action parameter (ßR/P), which was derived from the release enhancement effect (ERrelease) and skin permeation enhancement effect (ERpermeation) using seven CPEs with different physicochemical properties. Then the molecular mechanism was revealed by quantitative structure-activity relationship. Hydrophilic CPEs obtained highest ERrelease indicated that its enhancement action site was polymer matrix according to ßR/P value (>1), due to CPEs formed the strongest hydrogen bonds with polymer, thereby undermined drug-polymer interaction according to the results of FT-IR, MDSC and molecular docking. CPEs with high log P, molecular weight and polarizability showed highest ERpermeation, which indicated that its enhancement action site was skin according to its ßR/P value <1, due to it interacted with skin lipid strongly and obtained the lowest diffusion rate in skin. Thus, it increased the disruption level of highly ordered arrangement of intercellular lipid bilayers, which was characterized by ATR-FTIR, Raman, confocal laser scanning microscopy and molecular dynamics simulation. In conclusion, physicochemical properties of CPEs determined its enhancement action efficacy and sites in transdermal drug delivery process, which permitted rational selection of CPEs and the development of safer and more efficacious transdermal patch.

Investigation of Controlled Release Molecular Mechanism of Oil Phase in Spilanthol Emulsion: Development and In Vitro, In Vivo Characterization.

The aim of the present study was to develop a spilanthol emulsion and investigate the effect of oil and drug physicochemical properties on drug release and skin retention at molecular level. Formulation factors including oil, emulsifier, and humectant were investigated by in vitro skin retention/permeation study and the optimized formulation was evaluated in vitro and in vivo. In addition, the controlled release effect of oil was characterized using drug emulsion distribution study, drug release study, FT-IR, and molecular modeling. The optimized emulsion (squalane as oil phase) obtained the maximum skin retention (118.71 ± 10.30 µg/g), which significantly restored skin hydroxyproline content (23.99 ± 2.21 µg/g), compared with the positive group (14.75 ± 1.84 µg/g) and the negative group (15.55 ± 2.03 µg/g). It was caused by high drug release of squalene and good drug-skin miscibility. FT-IR and molecular modeling showed that spilanthol (SPI) interacted with squalene through Van der Waals force, which was weaker than a hydrogen bond formed with other oils, thus exhibited good drug release properties. And the released drug was stored in the skin due to good drug-skin miscibility, which was proved by miscibility calculation and molecular modeling. In conclusion, an effective emulsion was developed and the controlled release effect of oil phase was proved through drug-excipient interaction.

Molecular mechanism of ion-pair releasing from acrylic pressure sensitive adhesive containing carboxyl group: Roles of doubly ionic hydrogen bond in the controlled release process of bisoprolol ion-pair.

Though ion-pair strategy has been employed as an effective and promising method for controlling transdermal delivery of drugs, investigations into the underlying mechanisms involved in the controlled release process of ion-pairs are still limited. In the present study, a brand-new controlled release system combining acrylic pressure sensitive adhesive containing carboxyl group (carboxylic PSA) with ion-pair strategy was developed, and the molecular mechanism of ion-pair releasing from carboxylic PSA was systemically elucidated. Bisoprolol (BSP) and bisoprolol-lauric acid ion-pair (BSP-C12) were chosen as model drugs. Carboxylic PSA was designed and synthesized. Effect of ion-pair on controlling BSP release from carboxylic PSA was evaluated by in vitro drug release study, in vitro skin permeation study and pharmacokinetic study. Molecular mobility of PSA, along with the strength of drug-PSA interaction was evaluated by thermal analysis and dielectric spectroscopy. Molecular details of drug-PSA interaction were identified by FTIR, XPS and Raman. Roles of drug-PSA interaction in the controlled release process were clarified by molecular modeling. Results showed that BSP-C12 patch demonstrated a controlled release drug plasma profile, with lower Cmax (193 ±â€¯63 ng/mL) and longer MRT (19.9 ±â€¯3.4 h) compared to BSP patch (Cmax,BSP = 450 ±â€¯28 ng/mL, MRTBSP = 7.9 ±â€¯0.9 h). Besides, there was no significant difference between the AUC of BSP-C12 and BSP patch. It turned out that instead of PSA molecular mobility, molecular interaction between ion-pair and PSA played a dominant role in the controlled release process of BSP: as illustrated by FTIR, Raman and molecular docking, the ionic interaction between BSP-C12 and PSA determined the amount of BSP released, namely the thermodynamic process; while the doubly ionic hydrogen bond between BSP-C12 and PSA-COO- controlled the release rate, which was the kinetic process. In conclusion, it was found that the doubly ionic hydrogen bond formed between carboxylic PSA and ion-pair controlled the release profile of BSP, which broadened our understanding about the molecular mechanisms involved in ion-pair controlled release transdermal patches and contributed to the design of controlled release TDDS.

The role of carboxyl group of pressure sensitive adhesive in controlled release of propranolol in transdermal patch: Quantitative determination of ionic interaction and molecular mechanism characterization.

Acrylic pressure sensitive adhesives (PSAs) are widely used in transdermal drug delivery system (TDDS). However, there was little research about the quantitative relationship between drug release and drug-PSAs interaction. In this study, five acrylic PSAs with different molar fraction of carboxyl group were designed and synthesized. Propranolol (PRO) was used as model drug to evaluate release profiles in the PSAs in vitro and in vivo. The drug release percent in the PSAs were 81.66, 78.22, 51.66, 21.81 and 11.73%, and their release behaviors were decreased with carboxyl group content of PSAs. Furthermore, it was found that quantity of carboxyl group of PSAs was equal to residual drug by the quantitative determination. In addition, the ionic interaction between PRO and PSAs was confirmed by FT-IR and MDSC results qualitatively. Using the FT-IR, MDSC, Flory-Huggins interaction parameters and molecular dynamic simulation, interaction strength between drug and PSAs was determined quantitatively, which demonstrated that the drug release amount decreased linearly with interaction strength. Based on above results, we proposed that the PRO was possibly binding to the carboxyl group of PSAs one-by-one, which provided references for the accurate design of TDDS.

[Effects of Goutengsan on model of Alzheimer dementia in rats by AlCl3].

OBJECTIVE: Observe the effects of Goutengsan on SOD, MAO-B, GSH-PX, NO, LDH, index of brain, rate of death and so on in rats to study therapeutic effects and mechanism of Goutengsan on Alzheimer dementia (AD) model. METHOD: One hundred and twenty rats were randomly divided into 6 groups, 3 experimental groups of which were daily administrated with Goutengsan extract whereas the model and control groups were given NS (0.01 mL x g(-1)). Aniracetam at 0.1 g x kg(-1) served as a positive control. At the 5th day after administration, all groups except the control were administrated (ip) with AlCl3 (100 mg x kg(-1) ) for successive 50 days at 1 day interval. After administration, the death rate, body weight, training scores, brain index, MAO-B, SOD, GSH-Px in brain and NO, LDH in serum were determined. RESULT: The brain index, SOD, GSH-Px activities as well as NO content of drug-treated groups were strikingly higher that of model group, and had not obvious difference from that of normal group except content of LDH was higher. CONCLUSION: Goutengsan could increase the brain index, cut down the rate of death, stable increase of body weight, promote the endogenous antioxidant activity, enhance the clearance of lipid peroxide and other metabolic waste, inhibit the MAO-B activity, reduced the leakage of LDH and maintain the content of NO at a normal level. Therefore Goutengsan could protect cells, delay senile, improve symptoms of AD.