Application of exosomes in brain-targeted delivery / 药学学报

Brain-targeted delivery plays an important role in the diagnosis and treatment of neurological diseases, but the existence of blood brain barrier (BBB) limits the development of brain-targeted delivery. As cell-derived nanovesicles, exosomes can participate in the transportation of substances between cells to mediate the communication between cells to play a biological regulatory role in vivo. Due to the low immunogenicity, low toxicity, high engineering and natural crossing over BBB, exosomes play an important role in brain-targeted delivery. In this paper, the composition of exosomes, the mechanism of brain targeted delivery and its role in various brain diseases are systematically described.

The repellent effect of tea tree oil emulsion on leeches / 药学学报

Leech bites usually lead to more bleeding, and dermal tissue is damaged to form lifelong scars. If leeches enter the body cavity, it will be more dangerous. Therefore, there is an urgent need to develop effective repellents. In this study, oil in water (O/W) emulsion of tea tree oil was prepared with tea tree oil as the main ingredient, and konjac glucomannan (KGM), ethyl cellulose (EC) as the main excipients. The filter-paper ring method and repellent test in water were used to evaluate the repellent effects on leeches. The animal experiments were approved by the Ethics Committee of Academy of Military Medical Sciences and were conducted in accordance with relevant guidelines and regulations. The activities of acetylcholinesterase (AchE), glutathione S-transferase (GST) and carboxylesterase (CarE) in vivo were measured to clarify the repellent mechanisms. The results showed that a uniform and stable tea tree oil emulsion was successfully prepared, which has excellent hydrophilicity and can effectively repel leeches. The tea tree oil emulsion has a good repellent effect on leeches, which can avoid the volatilization of tea tree oil and prolong the effective repelling time. The novel formulation of tea tree oil provides a new idea for repelling effects with long time and high efficiency based on similar essential oil.

Anti-tumor nanoscale drug delivery systems based on photodynamic therapy / 药学学报

Photodynamic therapy (PDT) is a therapeutic strategy by which photosensitizers are excited by specific light irradiation to produce singlet oxygen for killing the surrounding cells. The advantages of PDT include weak invasion, slight side effect, and low resistance. The advantages of nanoscale drug delivery systems (DDS) include tumor-targeting, sustained release, and environmental-sensitivity. The combination of PDT and nanoscale DDS would likely lead to tumor targeting of photosensitizers and enhance their antitumor effectiveness. This review discusses the mechanism of PDT, photosensitizer-loaded nanoscale formulations, the combination of PDT and other antitumor therapies, and summarizes the applications and prospects of anti-tumor nanoscale DDS based on PDT. This review is a useful reference for its clinical application.

The combined therapeutic effects of 5-aminolevulinic acid cubic liquid crystal and light needles for basal cell cancer / 药学学报

The article was to study the effect of local photodynamics therapy combined with carbon dioxide lattice laser - "light needles" for the treatment of basal cell carcinoma (BCC). 5-Aminolevulinic acid (5-ALA) cubic liquid crystal using glyceryl monostearate (GMO) as the substrate was prepared. The cytotoxicity of 5-ALA cubic liquid crystal combined with light needles in vitro were evaluated. The pharmacodynamics study of 5-ALA cubic liquid crystal combined with light needles of high or low energy for BCC was carried out based on the pathological changes, tumor volume, vascular endothelial growth factor (VEGF) expression and the recurrence rate, which has been approved by the Ethics Committee of Beijing Institute of Radiation Medicine. The cubic liquid crystal was isotropic with the lattice of PN3M. The cytotoxicity of 5-ALA cubic liquid crystal combined with light needles was much higher than that of 5-ALA or light needles alone. Compared with light needles or photodynamic therapy alone, 5-ALA cubic liquid crystal combined with light needles of high energy could prevent the BCC metastasis and of low energy could inhibit BCC growth. It demonstrated the obvious therapeutical effects for BCC. 5-ALA cubic liquid crystal combined with light needles can effectively treat BCC, which provides a new choice for clinical BCC treatment.

Research progress of focused ultrasound combined with microbubbles to open blood-brain barrier for brain-targeted delivery / 药学学报

Blood-brain barrier (BBB) is the most challengeable obstacle for brain-targeted drug delivery. The combination of focused ultrasound (FUS) and microbubbles provides a new way for brain-targeted drug delivery across BBB based on the cavitation effect. This review briefly described the recent research of FUS combined with microbubbles to enhance the BBB permeability for brain-targeted drug delivery. The contents included the FUS mechanism, the types of the commercial microbubbles, shell materials, inner gas and preparation techniques of microbubbles, the opening mechanism of FUS with microbubbles, and the safety consideration. FUS combined with microbubbles may be the effective strategy to improve the BBB permeability for brain-targeted delivery, which could provide references for the clinical applications.

Application of environmentally sensitive hydrogels in drug delivery / 药学学报

Environmentally sensitive hydrogels are a novel formulation that has developed rapidly in recent years. It could form semi-solid with good adhesion in the topical sites based on different physiological environments. Its long local retention time is conducive for sustained drug release, and the preparation process is relatively simple and easy to realize industrialization. This review summarized the categories, commonly used polymer, and different administration routes based on the recently published literatures. According to different response factors, it can be divided into temperature, pH, ion, light, and multiple sensitive hydrogels, among which temperature-sensitive hydrogels are the most common. The most commonly used polymers include chitosan, poly N-isopropyl acrylamide, and poloxamer. There are different administration routes for environmentally sensitive hydrogels, such as transdermal, ophthalmic, nasal, oral, vaginal, rectal, injection, etc. Environmentally sensitive hydrogels have broad prospects in clinical application.

Intranasal tetrandrine temperature-sensitive gel for treatment of post-traumatic stress disorder / 药学学报

The traditional systemic treatment of post-traumatic stress disorder (PTSD) requires a long time period for an effect and has obvious side effects. In this study, tetrandrine temperature-sensitive gel (TTG) was prepared for treatment of PTSD in mice by nasal administration. TTG was prepared with poloxamer as matrix, the gelation temperature was suitable (<32 ℃) and the gelation time was short (1.32 min). Rheology experiments demonstrated that TTG has temperature sensitivity. In vivo imaging system of small animals proved that TTG nasal cavity retention time was so long. The cilia toxic test of toad showed that the formulation was safe. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. The mice were randomly assigned into healthy group, model group and TTG group. The PTSD model of mice was established by single prolonged stress (SPS) and foot-shock method to generate anxiety and fear behavior. On the day 0 of TTG administration, SPS model mice were evaluated by the elevated plus maze (EPM). Percentages of open arm entries number (OE), latency of open arm entries (OL) and the residence time of open arm entries (OT) all indicated that the SPS model was successfully established. On the 7th day of TTG administration, TTG increased the OE and OT, decreased the OL of SPS mice. The feard behavior of mice in the foot-shock model was tested using conditioned fear box, 7 days of TTG treatment can reduce the freezing time of the mice obviously. The pathological changes of hippocampus, prefrontal cortex and amygdala were observed by H&E histological sections and c-fos immunohistochemical expression. The main influenced areas of PTSD were revealed to be the CA1 of hippocampus, prefrontal cortex and amygdala. All of the above indicated that TTG is a convenient, safe and effective drug for PTSD treatment, and will provide a new choice for clinical management of PTSD.

3D printing technology in drug delivery system / 国际药学研究杂志

Three-dimensional (3D) printing,a type of rapid prototyping technology,is based on a digital model file and prints layer-by-layer using adhesive materials,such as powdered metal or plastic.3D printing has attracted much attention in the pharmaceutical field because of the various advantages,such as simple operation,good flexibility,high repeatability,wide adaptability,and more importantly,customized service.Currently,it is used in formulations of immediate release,sustained release,implants,etc.Recently,the integration of medical devices and drugs with 3D printing has been gaining popularity.This review not only summarizes the latest progress in techniques,materials,and pharmaceutical dosage forms used in drug delivery system with 3D printing,but also analyzes its advantages and limitations,with the hope of providing reference for the development and application of 3D printing technology in drug delivery.This novel drug delivery system will bring new vitality to individualized medication.

Enhanced anti-asthma effect of white mustard seed varnish cataplasm by iontophoresis and sonophoresis / 药学学报

Topically applied traditional Chinese medicines (TCM) generally show low transdermal rates and doses, leading to weak therapeutic efficacy. Here, cataplasm of white mustard seed varnish was prepared. The effects of iontophoresis and sonophoresis on the transdermal delivery of this TCM and its anti-asthma effect were evaluated. Active components of white mustard seed, rhizoma corydalis and Radix Kansui were obtained after alcohol extraction, respectively. The volatile oil in Asarum Heterotropoides were obtained with volatile oil extraction equipment. The drug loading ratio of cataplasms was 17% (w/w). Franz cell diffusion method was used to evaluate the accumulated permeation amount and the steady-state transdermal absorption rate of sodium thiocyanate. The improvement of sonophoresis on transdermal absorption was higher than that of iontophoresis.Asthma model of guinea pigs were established. Cataplasms of white mustard seed varnish were applied on the back of guinea pigs. Iontophoresis and sonophoresis obviously promoted the transdermal absorption and enhanced anti-asthma efficacy of white mustard seed varnish cataplasms. Pathological analysis showed that iontophoresis and sonophoresis significantly alleviated inflammation. Compared with the model group, IL-4 and IgE levels in the cataplasm group, cataplasm/iontophoresis group, cataplasm/sonophoresis group decreased obviously, although the IFN-γ levels markedly increased. Moreover, the therapeutic efficacy of cataplasm/sonophoresis group was the best in all the groups, even leading to levels similar to that of healthy animals. Iontophoresis and sonophoresis are effective methods to promote transdermal absorption of cataplasms. Moreover, the effect of sonophoresis is higher than that of iontophoresis. Physical penetration improvement techniques provide a novel insight for the wide application of transdermal TCM.

Application of chitosan in delivery of active natural products / 国际药学研究杂志

Chitosan,a natural polysaccharide,has attracted increasing attention as an excellent carrier for drug delivery.The advantages of chitosan include its good biocompatibility,biodegradability and non-toxicity.Polyphenol,flavone,coumarin,terpenes,alkaloids are important active natural products for disease treatment.Curcumin,paclitaxel,resveratrol,podophyllotoxin,vincristine,cannabidiol,triptolide are all remarkable molecules of bioactive natural products.However,most of them cannot be made into appropriate formulations due to their poor stability.It is imperative to select an appropriate drug delivery system to improve the stability of natural products.This review summarizes the recent progress related to chitosanbased drug delivery system for natural product,involving nanoparticles,hydrogels,microspheres,films,nanofibers,sponges and liposomes.In addition,this review describes the characteristics of chitosan in promoting wound healing,inhibiting bacterial growth,treating tumors and osteoarthritis.It seems that chitosan will be a promising and important excipient for novel formulations of bioactive natural products.

Effects of Panax Notoginseng Saponins Combined with Total Flavonoids from Epimedium on Decline in Testicular Reproductive Function of Natural Aging Rats / 中国中医药信息杂志

Objective To investigate the effects of panax notoginseng saponins (PNS) combined with total flavonoids from epimedium (TFE) on testicular dysfunction in natural aging rats; To discuss its mechanism of action. Methods Thirty 18-month old male SD rats were randomly divided into natural aging group, PNS combined with TFE low and high dose groups, with 10 rats in each group. Another 10 2-month old rats were set as young control group. PNS combined with TFE low and high dose groups were given gastric gavage of 10 mg/kg PNS combined with 10 mg/kg TFE, and 20 mg/kg PNS combined with 20 mg/kg TFE, respectively. Rats in young control group and natural aging group were given saline for 6 d each week, lasting for 4 months. Then, rats were sacrificed, and the testes were obtained to calculate the testicular weight and the testicular index. The testicular tissue morphology was observed by using HE staining. Testicular germ cell apoptosis was detected by using TUNEL method. The levels of Bcl-2, Bax and γ-H2 AX protein expression in testicular tissue were detected by Western blot. Results Compared with natural aging group, low and high dose of PNS combined with TFE significantly elevated the testicular weight and testicular index, improved the histological changes of testicular seminiferous tubule, significantly reduced number of apoptosis of spermatogenic cells in the testis, upregulated the expression of Bcl-2 protein in the testis, downregulated the expression of Bax and γ-H2 AX protein, and decreased the ratio of Bax/Bcl-2. Conclusion PNS combined with TFE can improve testicular dysfunction in natural aging rats by inhibiting apoptosis and DNA damage of germ cells.

Curcumin hydrogel combined with photodynamics to treat acne / 国际药学研究杂志

Objective To demonstrate the therapeutic effect of curcumin hydrogel combined with photodynamics on acne. Methods Sieving and ultrasound/high pressure homogenization were used to prepare curcumin micropowder.Curcumin-loaded hydro?gel was prepared with Poloxamer 407 and its rheological characteristics were evaluated.The antibacterial activity of curcumin hydrogel irritated with 657 nm laser was assayed by a hole-punching method.Acne model on rabbit ears war established.Fifteen New Zealand white rabbits were randomly divided into five groups:the model group,tretinoin cream group,illumination group,curcumin hydrogel group,and curcumin hydrogel/illumination group.The therapeutic effects on acne were evaluated by the morphological and histopatho?logical examination.Results The micropowdered curcumin prepared with ultrasound/high pressure homogenization had smaller size and more uniform distribution(size range:5-20 μm.)than the sieving-prepared curcumin micro-powders(10-45 μm).The prepared hydrogels being a pseudoplastic fluid had the properties of gelatin.The antibacterial effect of curcumin hydrogel/illumination was bet?ter than that of curcumin hydrogel.The inhibition zone diameters were(9.4±0.92)and(12.57±1.12)mm for the curcumin hydrogel and the curcumin hadrogel/illumination groups,respectively.The therapeutic effect for the treatment of acne on the rabbit ears with ac?ne was better in the curcumin hydrogel/illumination group than in both the illumination and the curcumin hydrogel groups. Conclu?sion Curcumin hydrogel combined with photodynamic therapy showed better therapeutic efficacy on acne treatment.It provides an ideal choice for acne treatment.

Curcumin temperature-sensitive in situ hydrogels for treatment of vaginal candidiasis / 国际药学研究杂志

Objective To investigate the therapeutic effect of curcumin in situ hydrogels for treatment of vaginal candidiasis. Methods In situ hydrogels were prepared using poloxamer 407 and 188 as the gel matrix.Gelation temperature,gelation time and rheological characteristics were determined.Mice models with vaginal candidiasis were established.The animals were divided into six groups:the healthy mice group,the model group,the positive control group(ketoconazole cream),curcumin-loaded in situ hydrogels of 0.025,0.10 and 0.20 g/ml.Before treatment and after the fourth and eighth treatments,the vaginal smears were collected and Gram-stained.The vagina washings fluid of mice were collected to determine DNA of Lactobacillus.On 8thday,the mice were sacrificed and the vaginal tissues were excised for pathological detection.Results The gelation temperature and time of in situ hydrogels were 29℃and 2′30″,respectively.Rheological profiles demonstrated that it showed good retention effect in vivo.Compared with the model group, curcumin hydrogels of 0.025,0.10 and 0.20 g/ml could inhibit the growth of Candida albicans,inhibit vaginal mucosal edema,inflam?matory hyperplasia,and decrease the expression of inflammatory factors including TNF-α(P<0.01)and IL-1β(P<0.01).Howev?er,curcumin hydrogels could not influence the growth of lactobacillus in the vagina.It indicated that curcumin hydrogels did not de?pend on lactobacillus to treat fungal vaginitis.Conclusion Curcumin in situ hydrogels could inhibit candidiasis growth,decrease ede?ma of vaginal mucosa and inflammatory hyperplasia,and reduce the expression of inflammatory factors.It provides a novel choice for the treatment of clinical vaginal candidiasis.

Brain-targeted nasal drug delivery systems for the treatment of neurodegenerative diseases / 国际药学研究杂志

Incidence of neurodegenerative diseases has been increasing year by year in the current aging society which interferes the living quality of the patients severely. Pathological changes in neurodegenerative diseases appeare in central nervous system CNS . The administration route of drugs to treat neurodegenerative diseases becomes a very important scientific research field. Part of drugs may cross over blood-brain barrier BBB to CNS by oral or injection administration. But most of drugs are distributed in the other tissues and might cause adverse reactions, such as gastrointestinal side-effects and arrhythmia. Moreover, the compliance of the aging patients is poor. They cannot adhere to administer multi-dose drugs for sereral times a day. Nasal drug delivery systems could deliver drugs to brains directly by nasal-brain route, avoiding BBB with high targeting ratio, high drug availability and good patients’ compliance. The review summarizes the major types of neurodegenerative diseases and their current therapeutic methods. The important obstacles for brain-targeted drug delivery, nose-brain routes and the factors influencing nasal absorption are introduced. More importantly, the principal formulations, recent research progress and the unsolved problems of brain-targeted nasal drug delivery systems are also reviewed.

Ultrasonic microbubbles for glioma-targeted drug delivery / 药学学报

Ultrasonic microbubbles were used to open blood-brain barriers (BBB) with a reversed and limited behavior feature in the study, which could improve the brain-targeted delivery of anti-tumor drugs. The glioma rat model was prepared. Low-frequency ultrasound was combined with microbubbles to affect the permeability of BBB compared with the permeability of independently administered Evans blue (EB) crossing BBB. Time point and length of ultrasound were investigated whether they affect the permeability of BBB and the damage of brain tissue. The effect of the growth time of glioma on BBB permeability was explored. Only glioma had a very little impact on BBB permeability. However, ultrasonic microbubbles opened the BBB with the features of temporary, limited and reversed behavior and improved EB and magnetic resonance imaging contrast agent penetrating BBB. A length of 30 s ultrasound is appropriate for opening BBB and no damage of brain tissue. Drugs should be injected before ultrasound so that they enter into brain as BBB opening. Ultrasonic microbubbles can open BBB effectively and safely, which improve drugs penetrating BBB under proper time point and length.

Preparation, in vitro and in vivo evaluation of cataplasm of white mustard seed varnish to prevent asthma / 中国中药杂志

The aim of the manuscript was to optimize formulations and preparation technologies of cataplasm of white mustard seed varnish, and to evaluate its anti-asthma effect on rats. The single factor experiments included spreading thickness, types of crosslinking agents, dihydroxyaluminum aminoacetate amount, sodium polyacrylate amount, types of adhesive agents with human sense as the evaluation index. Blank cataplasm matrix was optimized by the orthogonal experiment with the amount of glycerine, citric acid, and sodium carboxymethylcellulose as the major influential factors. Initial adhesive force, peeling strength and human sense were as the evaluation index. The optimized formulation of blank cataplasm were as followings: glycerine-water-ethanol-PEG400-dihydroxyaluminum aminoacetate-citric acid-sodium carboxymethylcellulose-sodium carboxymethylcellulose 2 : 8 : 0.8 : 0.4 : 0.07: 0.15 : 0.1 : 0.5. The active ingredients of white mustard seed, corydalis, and gansui root were extracted by alcohol extraction method. Asiasarum volatile oil was extracted by oil extractor. The optimized drug loading amount was 11% with initial adhesive force, peeling strength and human sense as the evaluation index. Asthma rats model were established by sensitized with ovalbumin and nose-scratching time as the evaluation index. High dose (17%) group of drug-loaded cataplasm had the obvious inhibition effect on nose-scratching time of rats (P = 0.037 < 0.05). In comparison, middle dose (11%), low dose (4%) and positive-control groups had no obvious inhibitive effect on rats. White mustard seed cataplasm supplied a novel choice for anti-asthma therapy. And the overall pharmacodynamics assessment will be carried out on molecular level in near future.

Improvement effect of iontophoresis on transdermal permeation of ferulic acid / 国际药学研究杂志

Objective: To evaluate the improvement of iontophoresis on the transdermal permeation of ferulic acid. Methods: The abdominal skin of mice was inserted in the modified Franz diffusion cell. Ferulic acid solution was the donor. The content of drug in the acceptor was quantified using the ultraviolet spectrophotometry. The influence of iontophoresis on permeation of ferulic acid was investigated within 10 hours. Results: The transdermal amount of ferulic acid was significantly improved by iontophoresis in vitro. Conclusion: Iontophoresis significantly improved ferulic acid permeation across skin. It could be a successful method to promote the skin permeation of other organic acids in traditional Chinese medicines.

In vitro pharmacodynamic evaluation of anti-HIV cholesteryl-phosphoryl zidovudine self-assemblies / 国际药学研究杂志

Objective To evaluate the anti-HIV activity of the self-assemblies of cholesteryl-phosphoryl zidovudine (CPZ) and provide evidence for the promising new anti-HIV drug. Methods CPZ self-assemblies were prepared. The MT4 cells infected by HIV-1 were the model to evaluate the anti-HIV activity of CPZ self-assemblies, which based on the generation of combined ceHs, was compared to that of the parent drug-zidovudine (AZT). The cytotoxicity of CPZ self-assemblies as evaluated by the MTT method. Phagocytosis of macrophage to CPZ self-assemblies was evaluated in RAW264. 7 ceHs. Results The anti-HIV activity of CPZ self-assemblies was much higher than that of AZT, with the half effective concentration (EC50) 1/10 to 1/50 that of AZT. The selectivity index (SI) was high, indicating that the self-assemblies were safe. Conclusion CPZ self-assemblies have high anti-HIV activity and is apromisinganti-HIV drug.

Anti-HIV macrophage-targeted drug delivery systems: Research advances / 国际药学研究杂志

Macrophages are the reservoir of human immunodeficiency virus (HIV). HIV hidden in the macrophages is replicated under appropriate conditions, leading to recurrence of AIDS. Macrophages are a new infection resource of HIV. Biomembrane penetration of current anti-HIV drugs is poor and the in vivo half life is short, resulting in high dose and frequent administration. Their distribution in macrophages is too liitle to eradicate the hidden HIV. Therefore, the development of anti-HIV macrophage-targeted delivery systems is very important. The review summarizes the nanoparticulate delivery systems of anti-HIV agents and their macrophage-targeted effects, involving nanoparticles, liposomes, nanosuspensions, self-assembled drug delivery systems, nanogels and nanocapsules, in order to provide a new strategy for the treatment of AIDS.