Single Delivery System Research Articles

Synthesis of Doxorubicin and miRNA Stimuli-Sensitive Conjugates for Combination Therapy.

Recent advances in combination therapy by using chemotherapeutic drugs and small noncoding RNAs have highlighted the need for optimization of such agents to allow their carriage in a single delivery system. This protocol details the synthesis of a doxorubicin prodrug, where a NHS coupling reaction was used to sensitize the drug to the proteolytic activity of tumor microenvironments. The design of a lipid-modified miRNA by an S-S coupling reaction is also described. Modification of both, doxorubicin and miRNA, facilitated their simultaneous incorporation into mixed micelles for use in combination therapy against tumor cells.

EUS-specific stents: Available designs and probable lacunae.

Interventional EUS has seen exponential growth in its indications and applications in the last decade.[1,2,3] Dedicated endoscopic devices for EUS-guided interventions are still limited. Up until recently, the tools used have been borrowed from other procedures such as ERCP. In interventional EUS, the linear-array echoendoscope allows a needle to be advanced under EUS-guidance from the upper gastrointestinal lumen to the biliary, pancreatic, or another adjacent intestinal lumen. Real-time puncture can be performed and provide the possibility of EUS-guided transluminal drainage (EUS-TLD). Plastic stents and conventional self-expandable metallic stents (SEMSs) were initially used but present several limitations due to their design.[1,4,5] They lack lumen-to-lumen anchorage and present migratory risks in the absence of stricture to hold them in place. Plastic stents are associated with potential pneumoperitoneum and bile peritonitis, whereas fully-covered SEMS (FCSEMS), despite preventing bile leak, will not maintain secure apposition between two nonadherent organs. Furthermore, their length often exceeds the anatomical requirement of a shorter transluminal anastomosis and predisposes them to obstruction as well as difficult positioning. With the rise in new EUS-guided interventional techniques, new tools, in particular, new stent designs have evolved to facilitate the various applications. A few EUS-specific stents have now become available for EUS-TLD.[4,5] We hereby review the stent designs and discuss lacunae to be addressed to improve the efficacy, safety, and ease of procedures.

FORMULATION AND EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM OF SALBUTAMOL SULFATE FOR THE CHRONOTHERAPY OF ASTHMA

Objective: The main objective of the present study was to design and evaluate a time-controlled single unit oral pulsatile drug delivery system containing salbutamol sulfate for the prevention of nocturnal asthma attacks.Methods: Drug containing core tablets (C1-C10) with different composition of superdisintegrants such as sodium starch glycolate, croscarmellose sodium, and crospovidone were prepared by direct compression technique. The fast disintegrating core tablet formulation was selected, and press-coated tablets (P1-P11) were prepared with different compositions of hydrophobic and hydrophilic polymers: Ethylcellulose-20 (EC-20), hydroxypropyl methylcellulose K4M, and low substituted hydroxypropyl cellulose (L-HPC LH11). The coating polymers were selected and quantified based on in vitro lag time and drug release profile in simulated gastric and intestinal fluids.Results: Formulation C10 with 7.5% crospovidone showed least disintegrating time, i.e., 0.31 min and was selected as the best immediate release core tablet. The press-coated tablet formulation P11 having 360 mg barrier layer of EC-20 and L-HPC LH11 in ratio 14:1 over the core tablet C10 showed rapid and complete drug release nearly after 6 h lag time. Accelerated stability studies of the optimized formulation P11 indicated no significant difference in release profile after a period of 6 months.Conclusion: The in vitro dissolution study showed that lag time before drug release was highly affected by the coating level and nature of coating polymer used. Time-controlled pulsatile release tablets can be prepared using press-coating techniques.

A polyethyleneimine-driven self-assembled nanoplatform for fluorescence and MR dual-mode imaging guided cancer chemotherapy

Multimode bioimaging probes with complementary advantages of imaging sensitivity and spatial resolution in a single drug delivery system have significant potential applications for clinical cancer diagnosis and chemotherapy. In this work, a polyethyleneimine-driven self-assembled lanthanide-doped CaF2 nanocluster was synthesized and used for fluorescence/MR imaging guided cancer chemotherapy. This nanocluster has an ordered pore structure and good cisplatin loading capacity. The release of cisplatin from this nanoplatform was triggered by acidic pH. In addition, this nanoplatform showed a high relaxation rate (4.91 mM−1 s−1) and fluorescence signal. The cell assay results indicated that the nanoplatform was effectively internalized by HeLa cells and showed a good fluorescence/MR imaging ability and cell inhibition effect. In vivo experiment, the nanoplatform displayed excellent fluorescence/MR imaging and anticancer activity. In addition, the side effects of cisplatin on vital organs were significantly mitigated. Thus, this multifunctional nanoplatform is an excellent candidate for fluorescence/MR imaging guided cancer chemotherapy.

Photoresponsive Nanovehicle for Two Independent Wavelength Light-Triggered Sequential Release of P-gp shRNA and Doxorubicin To Optimize and Enhance Synergistic Therapy of Multidrug-Resistant Cancer.

Prerelease of RNA molecules than chemotherapeutic drugs with a sufficient interval is a vital prerequisite for RNA/drug co-delivery strategy to overcome multidrug resistance (MDR) of cancer cells, but how to precisely control their release at different time points is still a grand challenge up to now. This study aims to on-demand remotely manipulate RNA and drug release in real time through single delivery system to sequentially play their respective roles for optimizing and enhancing their synergistic antitumor effects. To this end, a photoresponsive mesoporous silica nanoparticle (PMSN) is fabricated as a co-delivery vehicle of P-glycoprotein (P-gp) short-hairpin RNA (shRNA) and photocaged prodrug of doxorubicin (DOX), by which the orthogonal and sequential release of shRNA and DOX can be achieved using an external light. In our design, the cationic poly[2-( N, N-dimethylaminoethyl)methacrylate] is introduced onto the PMSN surface through a light-sensitive coumarin ester derivative linker to adsorb P-gp shRNA, whereas the photocleavable o-nitrobenzyl ester derivative-caged DOX is loaded into the inner pores of the PMSN. The PMSN is found to be effectively internalized by MDR cancer cells, and the release of the shRNA and DOX is demonstrated to be independently regulated by 405 and 365 nm light irradiations due to selectively cleaved coumarin and o-nitrobenzyl ester, resulting in enhanced drug retention, and finally bring out optimized and significantly improved chemotherapeutic effects both in vitro and in vivo for MDR cancer treatment, which might hold extensive application prospects in MDR cancer treatment in future.

Incorporation of beads into oral films for buccal and oral delivery of bioactive molecules

The association of alginate beads and guar-gum films in a single delivery system was idealized to promote a more effective buccal and oral delivery of bioactive molecules. A response surface method (experimental design approach) was performed to obtain optimal formulations of alginate beads to be incorporated into guar gum oral films as combined buccal and oral delivery systems for caffeine delivery. The combined formulation was further characterized regarding physicochemical properties, drug release, cell viability and buccal permeability. Beads average size, determined by dynamic light scattering (DLS), was of 3.37 ± 6.36 μm. Film thickness was set to 62 μm. Scanning electron microscopy micrographs revealed that beads were evenly distributed onto the film matrix and beads size was in accordance to data obtained from DLS analysis. Evaluation of Fourier-transform infrared spectra did not indicate the formation of new covalent bonds between the matrix of guar-gum films, alginate beads and caffeine. In vitro release assays by dialysis membrane allowed understanding that the combination of guar-gum films and alginate beads assure a slower release of caffeine when compared with the delivery profile of free caffeine from alginate beads or guar-gum films alone. MTT assay, performed on human buccal carcinoma TR146 cell line, allowed concluding that neither guar-gum film, alginate beads nor guar-gum film incorporated into alginate beads significantly compromised cell viability after 12 h of exposure. As demonstrated by in vitro permeability assay using TR146 human buccal carcinoma cell lines, combination of guar-gum films and alginate beads also promoted a slower release and, thus, lower apparent permeability (1.15E–05 ± 3.50E-06) than for caffeine solution (2.68E–05 ± 7.30E-06), guar-gum film (3.12E–05 ± 4.70E-06) or alginate beads (2.01E–05 ± 3.90E-06). The conjugation of alginate beads within an orodispersible film matrix represents an effective oral/buccal delivery system that induces a controlled release along with an enhanced intimate contact with cell layers that may promote higher in vivo bioavailability of carried drugs.

Malnutrition and school feeding programmes

Assessing national nutrition status is important due to the concern caused by malnutrition. The present article explores the questions and limitations associated with assessment of nutritional status in a community and the role of national school feeding programme to improve health. Nutritionists have been using for decades biological indicators (anthropometric, biochemical and clinical) and social determinants as essential parameters, in comparison with predetermined standards, but rarely consider that manifestations of nutrition deficiencies may only occur in severe cases and in the future. There is as yet no single effective approach to malnutrition management and it is unlikely that a single delivery system would suit all situations worldwide. Data on the most effective time and type of intervention are still lacking. Throughout decades United Nations initiated many Plans towards fighting hunger and recently for the Sustainable Development Goal of Zero Hunger by 2030. We set low expectations for the outcome of these international plans since most of the financial investments never fully reach the people in need. The malnutrition situation is worsened by the well-known conflict, socio-economic and climatic shocks, which affect production and access to key resources. Malnutrition and hunger must be tackled from infancy, preferably in programmes gathering the whole community of farmers around each school. We briefly review this complex approach and some positive outcomes.

Cyclometalated Iridium(III)-Complex-Based Micelles for Glutathione-Responsive Targeted Chemotherapy and Photodynamic Therapy

The integration of chemotherapy and photodynamic therapy (PDT) in a single delivery system is highly desirable for enhancing anticancer therapeutic efficacy. Herein, two cyclometalated Ir(III) complex-constructed micelles FIr-1 and FIr-2 were demonstrated for glutathione (GSH) activated targeted chemotherapy and PDT. The cyclometalated Ir(III) complexes were prepared by conjugating phosphorescent Ir(III) compounds with chemotherapeutic drug camptothecin (CPT) through GSH responsive disulfide bond linkages, and the Ir(III) complexes were then assembled with amphiphilic surfactant pluronic F127 via noncovalent encapsulation to afford micelles. The surfaces of the micelles were further decorated with folic acid as a targeting group. The micelles showed intense fluorescence that renders them with excellent real-time imaging capability. The release of free anticancer drug CPT from the micelles was realized through GSH-activated disulfide bond cleavage in tumor cells. In addition, the micelles were capable of generating singlet oxygen used for PDT upon visible light irradiation. On account of having folic acid targeting ligand, the micelles displayed greater cellular accumulation in folate receptor (FR) overexpressed HeLa cells than FR low-expressed MCF-7 cells, leading to selective cancer cell killing effect. As compared with solo therapeutic systems, the micelles with targeted combinational chemotherapy and PDT presented superior potency and efficacy in killing tumor cells at a low dosage. On the basis of these findings, the multifunctional micelles could serve as a versatile theranostic nanoplatform for cancer cell targeted imaging and combinational therapy.

Nanoparticle-releasing nanofiber composites for enhanced invivo vaginal retention.

Current approaches for topical vaginal administration of nanoparticles result in poor retention and extensive leakage. To overcome these challenges, we developed a nanoparticle-releasing nanofiber delivery platform and evaluated its ability to improve nanoparticle retention in a murine model. We individually tailored two components of this drug delivery system for optimal interaction with mucus, designing (1) mucoadhesive fibers for better retention in the vaginal tract, and (2) PEGylated nanoparticles that diffuse quickly through mucus. We hypothesized that this novel dual-functioning (mucoadhesive/mucus-penetrating) composite material would provide enhanced retention of nanoparticles in the vaginal mucosa. Equivalent doses of fluorescent nanoparticles were vaginally administered to mice in either water (aqueous suspension) or fiber composites, and fluorescent content was quantified in cervicovaginal mucus and vaginal tissue at time points from 24h to 7d. We also fabricated composite fibers containing etravirine-loaded nanoparticles and evaluated the pharmacokinetics over 7d. We found that our composite materials provided approximately 30-fold greater retention of nanoparticles in the reproductive tract at 24h compared to aqueous suspensions. Compared to nanoparticles in aqueous suspension, the nanoparticles in fiber composites exhibited sustained and higher etravirine concentrations after 24h and up to 7d, demonstrating the capabilities of this new delivery platform to sustain nanoparticle release out to 3d and drug retention out to one week after a single administration. This is the first report of nanoparticle-releasing fibers for vaginal drug delivery, as well as the first study of a single delivery system that combines two components uniquely engineered for complementary interactions with mucus.

Abuse-Deterrent Formulations in the Treatment of Chronic Pain

Prescription drug abuse is the fastest growing problem in the United States. According to the Centers for Disease Control and Prevention (CDC), enough opioid pain relievers were sold in 2010 to provide every adult in the United States with the equivalent of a typical dose of 5 mg of hydrocodone every 4 hours for 1 month. Many solutions have been proposed to address this problem, including treatment guidelines, political solutions (statutory changes), Risk Evaluation and Mitigation Strategy (REMS), and technological innovations. Many opioid products are manipulated (crushed, snorted, injected, etc.) to facilitate abuse. Since extended-release/long-acting (ER/LA) opioids contain a large amount of opioid contained in a single delivery system, they are a favorite target of abusers. In short, the goal of an abuser is to convert an ER/LA opioid into an immediate-release one. Abuse-deterrent formulations (ADFs) are intended to make manipulation more difficult or to make abuse of the manipulated product less attractive or less rewarding. One such technological solution is the development of ADFs for opioid pain medications. The Food and Drug Administration's (FDA) guidelines for industry released in 2015 establish the rationale and methodology for the development of ER/LA opioids that contain abuse-deterrent properties. The goal is to deter abuse, realizing that it is impossible to prevent abuse. Key words: abuse-deterrent formulations, abuse-deterrent opioids, CDC guidelines, FDA opioid guidelines, opioid abuse, opioid deaths, opioid diversion, opioid overdose, prescription drug abuse, REMS

Application of combination bubble liposomal amphotericin B and sonication has the dramatic effect on oral candidiasis

ObjectiveWe previously reported that ultrasound-mediated destruction of microbubbles might be an innovative non-invasive drug delivery system. AmBisome is a single bilayer liposomal drug delivery system consisting of unilamellar bilayer liposomes with amphotericin B, an antifungal drug, intercalated within the membrane. In the present study, we developed a novel fungicidal drug delivery system using ultrasound and bubble liposomal amphotericin B prepared by enclosing perfluoropropane gas within AmBisome. MethodsCandida albicans growth inhibition was determined by measuring optical density (OD), counting the number of colony forming units (CFU), and measuring the colony diameters. ResultTreatment with bubble liposomal amphotericin B and ultrasound significantly reduced the OD, CFU and diameter of colonies of C. albicans compared with ultrasound alone, liposomal amphotericin B alone, bubble liposomal amphotericin B alone, liposomal amphotericin B with ultrasound. ConclusionThese results indicate that treatment with bubble liposomal amphotericin B with ultrasound efficiently inhibited the growth of C. albicans, suggesting this novel approach may have a beneficial effect on the treatment of oral candidal disease.

Releasing rate optimization in a single and multiple transmitter local drug delivery system with limited resources

Drug delivery is one of the most important applications of molecular communication. Drug transmitters have limited resources in terms of energy and reservoir and these limitations should be taken into consideration when designing a drug delivery system. Drug molecules may also be expensive and releasing a large amount of them can have harmful effects on the healthy parts of the body. In this paper, we consider a multiple transmitter local drug delivery system in which the nearest transmitters to a randomly located tumor are activated to release drug molecules and guarantee the Least Effective Concentration (LEC) in every part of the tumor. We propose two different scenarios: a single transmitter drug delivery system for which the optimal rate of the transmitting nanomachine and the optimal density of deployed nanomachines are derived through formulations and simulations. Poisson distributed as well as regular square and hexagon grid deployments are investigated. We then extend it to a multiple transmitter drug delivery system for which the optimal allocated rate to each releasing transmitter is derived in order to minimize the total rate of release and maintain LEC in every part of the tumor. It is shown that activating multiple transmitters leads to a reduction in the total optimal release rate of drug molecules as well as improving the time duration between consecutive administrations.

Photodynamic Therapy with Liposomal Zinc Phthalocyanine and Tirapazamine Increases Tumor Cell Death via DNA Damage.

The efficacy of photodynamic therapy (PDT) in some solid tumors is limited by the poor biodistributive properties of conventional photosensitizers and a natural predisposition of tumor cells to survive hypoxia and oxidative stress. This study investigated the therapeutic potential of a third-generation photosensitizer, liposomal zinc phthalocyanine (ZnPC), in combination with the hypoxic cytotoxin tirapazamine (TPZ). TPZ induces DNA double strand breaks (DSBs) under hypoxic conditions and subsequent apoptosis via p53 signaling. Experiments were performed in tumor cells with functional p53 (Sk-Cha1) and dysfunctional p53 (A431). The combination therapy of TPZ and PDT induced DNA DSBs and cell cycle stalling and enhanced the cytotoxicity of PDT by exacerbating apopotic and non-apoptotic tumor cell death. These phenomena occurred regardless of oxygen tension and the mechanism of cell death differed per cell line. Liposomes containing both ZnPC and TPZ exhibited no dark toxicity but were more lethal to both cell types after PDT compared to ZnPC-liposomes lacking TPZ—an effect that was more pronounced under hypoxic conditions. In conclusion, TPZ is a suitable pharmaceutical compound to increase PDT efficacy by exploiting the post-PDT tumor hypoxia. The inclusion of TPZ and ZnPC into a single liposomal delivery system was feasible. The PDT strategy described in this study may be valuable for the treatment of PDT-recalcitrant tumors.

Better Management of Alcohol Liver Disease Using a 'Microstructured Synbox' System Comprising L. plantarum and EGCG.

Synergistic combination of probiotics with carbohydrate based prebiotics is widely employed for the treatment of various gut related disorders. However, such carbohydrate based prebiotics encourage the growth of pathogens and probiotics, equally. Aim of the study was (i) to explore the possibility of using epigallocatechin gallate (EGCG) a phenolic compound, as a prebiotic for L.plantarum; (ii) to develop and evaluate a microstructured synbox (microencapsulating both probiotic and EGCG together) in rat model of alcohol liver disease (ALD); and, (iii) to confirm whether the combination can address issues of EGCG bioavailability and probiotic survivability in adverse gut conditions. Growth enhancing effect of EGCG on L. plantarum (12.8±0.5 log 10 units) was significantly (p≤0.05) better than inulin (11.4±0.38 log 10 units), a natural storage carbohydrate. The formulated synbox significantly modulated the levels of alcohol, endotoxin, hepatic enzymes and restored the hepatoarchitecture in comparison to simultaneous administration of free agents. Additionally, using a battery of techniques, levels of various cellular and molecular markers viz. NF-kB/p50, TNF-α, IL12/p40, and signalling molecules TLR4, CD14, MD2, MyD88 and COX-2 were observed to be suppressed. Developed microbead synbox, as a single delivery system for both the agents showed synergism and hence, holds promise as a therapeutic option for ALD management.

Efficient cocktail chemotherapy by co-delivery of a hydrogen sulfide-releasing aspirin prodrug and paclitaxel via single nanoparticles

A cocktail composed of hydrogen sulfide-releasing aspirin (HS-ASP) and paclitaxel (PTX) in a single delivery system was formulated and provides a promising platform for the cocktail treatment of non-small cell lung cancer.

Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors.

It remains a substantial challenge to targetedly deliver drug to both primary tumors and metastatic lesions employing a single nanoparticle delivery system. Here aiming at the receptor for hyaluronic acid mediated motility (RHAMM or CD168), a specific receptor for hyaluronic acid (HA), the bioreductive responsive HA nanogels loaded doxorubicin were prepared. The targeting effects of HA nanogels in high RHAMM-expressed cancer cells, primary and metastatic tumors were investigated. It was found that HA nanogels show a strong in vitro and in vivo RHAMM-mediated cellular uptake and drug delivery. The cellular uptake of HA nanogels in high RHAMM-expressed LNCaP and H22 cells was far more than the uptake in low RHAMM-expressed NIH3T3 cells. The IC50 value of drug-loaded HA nanogels against H22 cells was lower than that of free drug. In vivo antitumor activity examinations showed that the HA nanogels not only had significantly superior antitumor efficacy in murine H22 and human LNCaP tumor-bearing mice but also exhibited much deep tumor penetration. The drug delivery of lymph node metastasis by systemically administering HA nanogels demonstrated that the HA nanogels could sufficiently increase drug concentration in metastatic lymph node by RHAMM-HA interaction and inhibit the growth of metastatic lymph node, even completely heal malignant lymph node metastasis. Thus, RHAMM-directed drug delivery is a promising therapy route for treating both primary and metastatic tumors.

Effective combination treatment of lung cancer cells by single vehicular delivery of siRNA and different anticancer drugs.

In recent years, lung cancer has become one of the fastest growing cancers in the world. Thus, the development of efficient combination therapy to treat lung cancer has attracted significant attention in the cancer therapy field. In this article, we developed a single vehicle drug delivery system, based on quantum dot (QD) nanoparticles, to deliver small interfering RNA (siRNA; target Bcl-2) and different anticancer drugs (carboplatin, paclitaxel, and doxorubicin) simultaneously for treating A549 lung cancer cells efficiently by combination therapy. The QD nanoparticles were conjugated with l-arginine (l-Arg) and different kinds of hydroxypropyl-cyclodextrins (HP-α-CDs, HP-β-CDs, and HP-γ-CDs) on the surface to form the delivery nanocarriers (QD nanocarriers). They were able to not only bind and transport the siRNA through electrostatic interactions with l-Arg residues but also accommodate various disparate anticancer drugs using different HP-CD modifications. Compared with free drug treatments, the use of QD nanocarriers to deliver Bcl-2 siRNA and different anticancer drugs simultaneously exerted a threefold to fourfold increase in cytotoxicity in A549 cells, which greatly improved the treatment efficacy through combined action. Furthermore, the QD nanocarriers could be used as a probe for real-time imaging of the drug delivery and release because of their strong fluorescence properties. These findings indicate that multifunctional QD nanocarriers hold great promise as a powerful tool for combination therapy for lung cancer.

Folate-Functionalized Magnetic-Mesoporous Silica Nanoparticles for Drug/Gene Codelivery To Potentiate the Antitumor Efficacy

An appropriate codelivery system for chemotherapeutic agents and nucleic acid drugs will provide a more efficacious approach for the treatment of cancer. Combining gene therapy with chemotherapeutics in a single delivery system is more effective than individual delivery systems carrying either gene or drug. In this work, we developed folate (FA) receptor targeted magnetic-mesoporous silica nanoparticles for the codelivery of VEGF shRNA and doxorubicin (DOX) (denoted as M-MSN(DOX)/PEI-FA/VEGF shRNA). Our data showed that M-MSN(DOX)/PEI-FA could strongly condense VEGF shRNA at weight ratios of 30:1, and possesses higher stability against DNase I digestion and sodium heparin. In vitro antitumor activity assays revealed that HeLa cell growth was significantly inhibited. The intracellular accumulation of DOX by confocal microscopy and fluorescence spectrophotometry showed that M-MSN(DOX)/PEI-FA were more easily taken up than nontargeted M-MSN(DOX). Quantitative PCR and ELISA data revealed that M-MSN/PEI-FA/VEGF shRNA induced a significant decrease in VEGF expression as compared to cells treated with either the control or other complexes. The invasion and migration phenotypes of the HUVECs were significantly decrease after coculture with MSN/PEI-FA/VEGF shRNA nanocomplexes-treated HeLa cells. The approach provides a potential strategy to treat cancer by a singular nanoparticle delivery system.

Hybrid systems based on “drug – in cyclodextrin – in nanoclays” for improving oxaprozin dissolution properties

A combined approach based on drug complexation with cyclodextrins, and complex entrapment in nanoclays has been investigated, to join in a single delivery system the benefits of these carriers and potentiate their ability to improve the dissolution properties of oxaprozin (OXA), a poorly water-soluble anti-inflammatory drug. Based on previous studies, randomly methylated ß-cyclodextrin (RAMEB) was chosen as the most effective cyclodextrin for OXA complexation. Adsorption equilibrium studies performed on three different clays (sepiolite, attapulgite, bentonite) allowed selection of sepiolite (SV) for its greater adsorption power towards OXA. DSC and XRPD studies indicated drug amorphization in both binary OXA-RAMEB coground and OXA-SV cofused products, due to its complexation or very fine dispersion in the clay structure, respectively. The drug amorphous state was maintained also in the ternary OXA-RAMEB-SV cofused system. Dissolution studies evidenced a clear synergistic effect of RAMEB complexation and clay nanoencapsulation in improving the OXA dissolution properties, with an almost 100% increase in percent dissolved and dissolution efficiency compared to the OXA-RAMEB coground system. Therefore, the proposed combined approach represents an interesting tool for improving the therapeutic effectiveness of poorly soluble drugs, and reducing the CD amount necessary for obtaining the desired drug solubility and dissolution rate increase.

Improved Oral Bioavailability Using a Solid Self-Microemulsifying Drug Delivery System Containing a Multicomponent Mixture Extracted from Salvia miltiorrhiza.

The active ingredients of salvia (dried root of Salvia miltiorrhiza) include both lipophilic (e.g., tanshinone IIA, tanshinone I, cryptotanshinone and dihydrotanshinone I) and hydrophilic (e.g., danshensu and salvianolic acid B) constituents. The low oral bioavailability of these constituents may limit their efficacy. A solid self-microemulsifying drug delivery system (S-SMEDDS) was developed to load the various active constituents of salvia into a single drug delivery system and improve their oral bioavailability. A prototype SMEDDS was designed using solubility studies and phase diagram construction, and characterized by self-emulsification performance, stability, morphology, droplet size, polydispersity index and zeta potential. Furthermore, the S-SMEDDS was prepared by dispersing liquid SMEDDS containing liposoluble extract into a solution containing aqueous extract and hydrophilic polymer, and then freeze-drying. In vitro release of tanshinone IIA, salvianolic acid B, cryptotanshinone and danshensu from the S-SMEDDS was examined, showing approximately 60%–80% of each active component was released from the S-SMEDDS in vitro within 20 min. In vivo bioavailability of these four constituents indicated that the S-SMEDDS showed superior in vivo oral absorption to a drug suspension after oral administration in rats. It can be concluded that the novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of both lipophilic and hydrophilic constituents of salvia. Thus, the S-SMEDDS can be regarded as a promising new method by which to deliver salvia extract, and potentially other multicomponent drugs, by the oral route.