HI-6-loaded PEGylated liposomes: an on-site first-aid strategy for acute organophosphorus agent poisoning.

Organophosphorus agents, also known as nerve agents, are very dangerous chemicals that were used as chemical warfare agents. HI-6 is one of the most promising reactivators which is effective in reactivating AChE inhibited by many nerve agents. However, the fast in-vivo clearance of HI-6 became a large barrier for first aid use under some sophisticated circumstances. In this study, PEGylated liposomes loading HI-6 were prepared and evaluated in vitro and in vivo. For PEG-LP-HI-6, the optimal formulation's loading efficiency and encapsulation efficiency were 6.47 ± 0.10% and 71.2 ± 1.15%, respectively. According to the pharmacokinetic results, compared with free HI-6 and LP-HI-6, the intravenous injection of PEG-LP-HI-6 significantly extended t1/2 (1.47 ± 0.29 h), MRT (1.44 ± 0.07 h), and improved the AUC of HI-6 in vivo. Drug concentrations in the CNS also increased after the intravenous administration of PEG-LP-HI-6. For in vivo treatment study, twenty minutes after poison exposure, the survival rate of animals in saline, free HI-6, LP-HI-6 and PEG-LP-HI-6 groups were 0, 0, 30% and 70%, respectively. Compared with the non-PEGylated liposomes group and free HI-6, PEG-LP-HI-6 could prolong the survival time of experimental animals and alleviate the neurotoxic symptoms, which demonstrated great potential as a first-aid strategy for acute organophosphorus agent poisoning.

Core-Shell Microspheres Prepared Using Coaxial Electrostatic Spray for Local Chemotherapy of Solid Tumors.

Local chemotherapy is an alternative therapeutic strategy that involves direct delivery of drugs to the tumor site. This approach avoids adverse reactions caused by the systemic distribution of drugs and enhances the tumor-suppressing effect by concentrating the drugs at the tumor site. Drug-loaded microspheres are injectable sustained-release drug carriers that are highly suitable for local chemotherapy. However, a complex preparation process is one of the main technical difficulties limiting the development of microsphere formulations. In this study, core-shell structured microspheres loaded with paclitaxel (PTX; with a core-shell structure, calcium alginate outer layer, and a poly (lactic acid-co-glycolic acid) copolymer inner layer, denoted as PTX-CA/PLGA-MS) were prepared using coaxial electrostatic spray technology and evaluated in vitro and in vivo. PTX-CA/PLGA-MS exhibited a two-stage drug release profile and enhanced anti-tumor effect in animal tumor models. Importantly, the preparation method reported in this study is simple and reduces the amount of organic solvent(s) used substantially.

Synergistic enhancement of the emergency treatment effect of organophosphate poisoning by a supramolecular strategy.

Poisoning by organophosphorus agents (OPs) is a serious public health issue across the world. These compounds irreversibly inhibit acetylcholinesterase (AChE), resulting in the accumulation of acetylcholine (ACh) and overstimulation of ACh receptors. A supramolecular detoxification system (SDS) has been designed with a view to deliver pyridine-2-aldoxime methochloride (PAM) with a synergistic inhibition effect on the ACh-induced hyperstimulation through host-guest encapsulation. NMR and fluorescence titration served to confirm the complexation between carboxylatopillar[6]arene (CP6A) and PAM as well as ACh with robust affinities. Patch-clamp studies proved that CP6A could exert an inhibition effect on the ACh-induced hyperstimulation of ACh receptors. Support for the feasibility of this strategy came from fluorescence imaging results. In vivo studies revealed that complexation by CP6A serves to increase the AChE reactivation efficiency of PAM. The formation of the PAM/CP6A complex contributed to enhance in a statistically significant way the ability of PAM not only to relieve symptoms of seizures but also to improve the survival ratio in paraoxon-poisoned model rats. These favorable findings are attributed to synergistic effects that PAM reactivates AChE to hydrolyze ACh and excess ACh is encapsulated in the cavity of CP6A to relieve cholinergic crisis symptoms.

Ilomastat contributes to the survival of mouse after irradiation via promoting the recovery of hematopoietic system.

Ilomastat, a broad-spectrum inhibitor of matrix metalloproteinases (MMPs), has drawn attentions for its function in alleviating radiation damage. However, the detailed mechanisms of Ilomastat's protection from animal model remain not fully clear. In this study, the C57BL/6 mice were pre-administrated with Ilomastat or vihicle for 2 h, and then total body of mice were exposed to 6 Gy of γ-rays. The protective effect of Ilomastat on the hematopoietic system in the irradiated mice were investigated. We found that pretreatment with Ilomastat significantly reduced the level of TGF-ß1 and TNF-α, and elevated the number of bone marrow (BM) mononuclear cells in the irradiated mice. Ilomastat pretreatment also increased the fraction of BM hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) at day 30 after irradiation, and protected the spleen of mouse from irradiation. These results suggest that Ilomastat promotes the recovery of hematopoietic injury in the irradiated mice, and thus contributes to the survival of mouse after irradiation.

Brain-targeted delivery of obidoxime, using aptamer-modified liposomes, for detoxification of organophosphorus compounds.

Effective intracerebral delivery acetylcholinesterase (AChE) reactivator is key for the acute organophosphorus (OPs) poison treatment. However, the blood-brain barrier (BBB) restricts the transport of these drugs from blood into the brain. Herein, we developed transferrin receptor (TfR) aptamer-functionalized liposomes (Apt-LP) that could deliver AChE reactivator (obidoxime) across the BBB to act against paraoxon (POX) poisoning. The aptamer had strong affinity for TfR and was modified with 3'-inverted deoxythymidine (dT) to improve serum stability. The uptake of Apt-LP by bEnd.3 cells was significantly higher than that of non-targeting liposomes. The ability of Apt-LP to penetrate intact BBB was confirmed in in vitro BBB mice model and in vivo biodistribution studies. Treatment of POX-poisoned mice with Apt-LP-LuH-6 reactivated 18% of the brain AChE activity and prevented brain damage to some extent. Taken together, these results showed that Apt-LP may be used as a promising brain-targeted drug delivery system against OPs toxicity.

"Oil-soluble" reversed lipid nanoparticles for oral insulin delivery.

BACKGROUND: In this study, we aimed to design a novel oral insulin delivery system, named "oil-soluble" reversed lipid nanoparticles (ORLN), in which a hydrophilic insulin molecule is encapsulated by a phospholipid (PC) shell and dissolved in oil to prevent the enzymatic degradation of insulin. ORLN was characterized by transmission electron microscopy and dynamic light scattering. RESULTS: In vitro enzymatic stability studies showed higher concentrations of insulin in cells incubated with ORLN-encapsulated insulin than in those incubated with free insulin solution in artificial intestinal fluid (pH 6.5). The protective effect of ORLN was attributed to its special release behavior and the formulation of the PC shell and oil barrier. Furthermore, an in vivo oral efficacy study confirmed that blood glucose levels were markedly decreased after ORLN administration in both healthy and diabetic mice. In vivo pharmacokinetic results showed that the bioavailability of ORLN-conjugated insulin was approximately 28.7% relative to that of the group subcutaneously administered with an aqueous solution of insulin, indicating enhanced oral absorption. CONCLUSIONS: In summary, the ORLN system developed here shows promise as a nanocarrier for improving the oral absorption of insulin.

Taste masking of water-soluble drug by solid lipid microspheres: a child-friendly system established by reversed lipid-based nanoparticle technique.

OBJECTIVES: A child-friendly taste-masking strategy using solid lipid microsphere (SLM) has been proposed to obscure the undesirable taste of some water-soluble drugs. In this study, the reversed lipid-based nanoparticle (RLBN) technique was used to encapsulate a water-soluble drug to facilitate the preparation of SLM. METHODS: The model drug used was atomoxetine hydrochloride (ATX), and a three-step method was used to prepare ATX-RLBN. Taste-masking microsphere (ATX-RLBN-SLM) was prepared by the spray chilling method. The drug release mechanism was studied by high-performance liquid chromatography and scanning electron microscopy. Moreover, in vitro taste evaluation method was established and ATX bioavailability was investigated employing pharmacokinetic studies. KEY FINDINGS: The obtained ATX-RLBN-SLM had smooth spherical particles with a size of about 80 µm. The drug encapsulation and loading efficiencies were 98.28% ± 0.59% and 0.89% ± 0.04%, respectively. In vitro drug release studies showed that nearly 96% drug was retained in the microspheres within 10 min at pH 6.8 and a complete release was triggered by lipase, accompanied by variation in the morphology. Taste assessment revealed that ATX-RLBN-SLM could efficiently mask the bitter taste and improved the bioavailability of ATX. CONCLUSIONS: Atomoxetine hydrochloride-reversed lipid-based nanoparticle-solid lipid microsphere exhibited excellent taste-masking effect with negligible leakage in the oral cavity environment and thorough collapse upon lipase stimulation, simultaneously enhancing the bioavailability of ATX. The study paves a new way to efficiently mask the undesirable taste of some water-soluble drugs.

Why is glycocholic acid sodium salt better than deoxycholic acid sodium salt for the preparation of mixed micelle injections?

Classical mixed micelle systems make excellent parenteral drug carriers for lipophilic or poorly soluble drugs, but many formulations details are not fully understood and need further study. Thus, we constructed mixed micelle systems with lecithin and either glycocholic acid sodium salt or deoxycholic acid sodium salt in order to investigate the differences between the bile salts. Vitamin K1, a lipid-soluble drug, was encapsulated in the mixed micelles, and the influence of bile salts on the quality and stability of the mixed micelle systems was analyzed. Both bile salts displayed similar profiles, and the amounts of bile salts used in formulating clear solutions did not differ. Mixed micelle systems formed from glycocholic acid sodium were physically stable at low pH levels (5.5), whereas those formed from deoxycholic acid required higher pH (>8.5). High pH levels hurt active pharmaceutical ingredients that are prone to hydrolytic and oxidative degradation. Hence, when mixed micelle systems formed from deoxycholic acid sodium were sterilized, unexpected chemical unstability occurred. Therefore, we conclude that glycocholic acid sodium salt is more suitable than deoxycholic acid sodium salt for the preparation of mixed micelle injections.

Reversed Lipid-Based Nanoparticles Dispersed in Iodized Oil for Transarterial Chemoembolization.

Transarterial chemoembolization (TACE) is a promising treatment for patients suffering from unresectable liver malignancy. A coarse emulsion of doxorubicin solution and iodized oil is widely used in clinical practice. However, this coarse emulsion lacks sufficient physical stability and can split into water and oil very quickly. Furthermore, most chemotherapeutics are quickly released into systematic circulation, causing serious adverse effects. In this study, we aimed to prepare reversed lipid-based nanoparticles (RLBNs) dispersed in iodized oil as nanocarriers for the delivery of hydrophilic chemotherapeutics. Unlike a simple mixture of drug solution and oil, RLBN is a homogenous system and possesses a hydrophobic nanostructure that has high dispersibility in oils. Hydrophilic chemotherapeutics were entrapped in the polar core juxtaposed by highly biocompatible lipid materials, such as egg phospholipids. A sustained drug-release profile was observed in both in vitro and in vivo pharmacokinetics studies. The results of computed tomography showed that RLBN-doxorubicin-iodized oil could remain in the tumor region for more than 14 days and that the growth of tumors was effectively suppressed. Thus, the current results suggest that RLBN is a promising drug delivery system and is compatible with TACE treatment.

Delivering the Acetylcholine Neurotransmitter by Nanodrugs as an Effective Treatment for Alzheimer's Disease.

The current clinical symptomatic therapy for Alzheimer's disease involves increasing acetylcholine levels in the brain by inhibiting acetylcholinesterase. However, the effectiveness of acetylcholinesterase inhibitors decreases as the disease progresses, leading to many side effects including over-inhibition of other enzymes and hepatic injury. Herein, we investigate the effects of the direct delivery of a low-dose of acetylcholine via human serum albumin nanoparticles to brain. This novel nanodrug improved both spatial learning and memory capability, whereas it reduced oxidative damage in mice. More importantly, damage to the liver or interference with the inherent neurotransmitter generation due to supplementation were almost absent. Our study is the first to demonstrate that supplementation of acetylcholine-loaded nanoparticles might offer a better therapeutic option in the ease of Alzheimer's disease.

A Novel Surfactant-free Lipid-based Formulation for Improving Oral Bioavailability of Loratadine Using Colloidal Silicon Dioxide as Emulsifier and Solid Carrier.

BACKGROUND: The purpose of this study was to develop an innovative surfactant-free lipidbased formulation (LF) for improving oral bioavailability of loratadine based on using solid particles colloidal silicon dioxide (CSD) as emulsifier and solid carrier. METHODS: Loratadine was dissolved in oil solution with the aid of co-solvent and LF formulations were prepared by a simple adsorption and milling technique. The LF Powder was evaluated in terms of angle of repose and X-ray powder diffraction. After dispersing and emulsifying in water, the particle size and morphology were also characterized. In vitro dissolution and pharmacokinetic behavior in vivo were also studied. RESULTS: Orthogonal design indicated that the amount of CSD in formulations had a major and significant influence on emulsification. The optimal formulation showed LF with good flowability and without crystallization or deposition of loratadine in it. CONCLUSION: After dispersing in water, an emulsion with the mean droplet size of 1.2µm was obtained. Although the dissolution of drug from LF was slower in vitro in acidic aqueous solution, pharmacokinetic studies in vivo showed that the bioavailability of loratadine increased 2.49-fold by CF compared to a commercial tablet.

Creation of an assessment system for measuring the bitterness of azithromycin-containing reverse micelles.

We aimed to develop a novel method for assessing the bitterness of azithromycin-containing reverse micelles (AM-containing RMs). Azithromycin-containing reverse micelles were prepared by processing Lipoid E80 and medium chain triglycerides via a freeze-drying method. The bitterness threshold of azithromycin was determined by human taste test, and an equation was derived to correlate the azithromycin concentrations and bitterness scores of standard solutions. Simulated salivary fluids and sampling times were fixed based on the drug release profile of AM-containing RMs, with Zithromax® (a commercial formulation of azithromycin) used as the control. The drug release concentrations from stimulated salivary fluids were then used to assess the bitterness of AM-containing RMs and Zithromax®. Afterward, the oral bioavailability of both formulations was evaluated by in vivo experiments in male Wistar rats. The results showed that the bitterness threshold of azithromycin standard solutions was between 25.3 µg/ml and 30.4 µg/ml. Thereafter, we calculated that the bitterness scores and the drug release concentrations of the azithromycin-containing reverse micelle formulation were similar to those of Zithromax® at each time point after 10 min of dispersal in simulated salivary fluid. In addition, the AUC0 - t after oral administration of AM-containing RMs was 1.75-fold (P < 0.05) higher than that of Zithromax®. In conclusions, a system for assessing bitterness was developed using an in vitro drug release evaluation method and a human taste test panel. We found that the bitterness of azithromycin was successfully masked by reverse micelles, which also improved the oral bioavailability of azithromycin compared to that of Zithromax®.

A novel core-shell lipid nanoparticle for improving oral administration of water soluble chemotherapeutic agents: inhibited intestinal hydrolysis and enhanced lymphatic absorption.

The oral administration of water-soluble chemotherapeutical agents is limited by their serious gastrointestinal side effects, instability at intestinal pH, and poor absorption. Aiming to solve these problems, we chose topotecan (TPT) as a model drug and developed a novel lipid formulation containing core-shell lipid nanoparticle (CLN) that makes the water-soluble drug to 'dissolve' in oil. TPT molecules can be encapsulated into nanoparticles surrounded by oil barrier while avoiding the direct contact with intestinal environment, thus easing the intestinal hydrolytic degradation and gastrointestinal (GI) irritation. Microstructure and mean particle size of TPT-CLN were characterized by Transmission Electron Microscope (TEM) and Dynamic Light Scattering (DLS), respectively. The average size of nanoparticles was approximately 60 nm with a homogeneous distribution in shapes of spheres or ellipsoid. According to in vitro stability studies, more initial form of TPT was observed in presence of lipid nanoparticle compared with free topotecan solution in artificial intestinal juice (pH 6.5). After oral administration of TPT-CLN in rats, AUC and Cmax of TPT were all increased compared with free TPT, indicating significant enhancement of oral absorption. Intestinal lymphatic transport was confirmed as the major way for CLN to enhance oral absorption of TPT by the treatment of blocking chylomicron flow. Lower GI irritation of TPT-CLN was observed in the gastrointestinal damage studies. The in vivo antitumor activity of TPT-CLN showed an improved antitumor efficacy by oral treatment of TPT-CLN compared to free TPT. From the obtained data, the systems appear an attractive progress in oral administration of topotecan.

Ilomastat, a synthetic inhibitor of MMPs, prevents lung injury induced by γ-ray irradiation in mice.

Lung injury is one of the pathological features in human or animal after radiation and the main side effect for patient after lung cancer radiotherapy. The efficient protective strategy still needs to exploit and the underlying mechanisms remain to be investigated. We found that the expression and activity of matrix metalloproteinases (MMPs) significantly increased at the early stage of radiation-induced lung injury (RILI). Pretreatment with Ilomastat, a synthetic inhibitor of MMPs, decreased the expression and activity of MMPs and significantly alleviated the lung inflammation and fibrosis in the irradiated mice, as well as enhanced the survival of irradiated mice. In addition, the levels of TGF-ß, IL-6, TNF-α and IL-1ß in the tissues dramatically reduced in the irradiated mice pretreated with Ilomastat. Furthermore, our experiments in vitro also showed that radiation significantly increased the MMPs activity, and Ilomastat pretreatment inhibited the activity of MMPs activated by irradiation and increased the cell survival. It is the first report, to our knowledge, to demonstrate that Ilomastat is a potential effective reliever for RILI and MMPs may play important roles in the process of RILI.

Reversed lipid-based nanoparticles dispersed in oil for malignant tumor treatment via intratumoral injection.

Intratumoral injection of anticancer drugs directly delivers chemotherapeutics to the tumor region, offering an alternative strategy for cancer treatment. However, most hydrophilic drugs spread quickly from the injection site into systemic circulation, leading to inferior antitumor activity and adverse effects in patients. Therefore, we developed novel reversed lipid-based nanoparticles (RLBN) as a nanoscale drug carrier. RLBNs differ from traditional nanoscale drug carriers in that they possess a reversed structure consisting of a polar core and lipophilic periphery, leading to excellent solubility and stability in hydrophobic liquids; therefore, hydrophilic drugs can be entrapped in RLBNs and dispersed in oil. In vivo studies in tumor-bearing Balb/c nude mice indicated remarkable antitumor activity of RLBN-DOX after a single injection, with effective tumor growth inhibition for at least 17 days; the inhibition rate was ∼80%. These results can be attributed to the long-term retention and sustained drug release of RLBN-DOX in the tumor region. In contrast, intratumoral injection of free DOX showed weaker antitumor activity than RLBN-DOX did, with the tumor size doubling by day 11 and tripling by day 17. Further, the initial burst of drug released from free DOX could produce detrimental systemic effects, such as weight loss. Histological analyses by TUNEL staining showed apoptosis after treatment with RLBN-DOX, whereas tumor cell viability was high in the free DOX group. Current results indicate that RLBNs show sustained delivery of hydrophilic agents to local areas resulting in therapeutic efficacy, and they may be a promising drug delivery system suitable for intratumoral chemotherapy.

Release Characteristics In Vitro and In Vivo of In Situ Gels for a Novel Peptide Compared with Low-Molecular-Weight Hydrophilic Drug.

BACKGROUND: The thermo-sensitive in situ gels based on copolymers are attractive as an injectable drug delivery carriers for sustained releasing of hydrophilic drugs. The purposes of this work are to investigate the release behavior in vitro and pharmacokinetic profiles in vivo of peptide and lowmolecular- weight hydrophilic drug loaded in the in situ gels. METHODS: A triblock copolymer PLGA-PEG-PLGA (1402-1000-1402) 1115A (1115A) was synthesized and its rheological and gelatin properties were evaluated. The temperature-sensitive in situ gels based on 1115A of LXT-101, a polypeptide drug, were prepared and the release characteristics in vitro and pharmacokinetic behavior in vivo were investigated. Meanwhile, naltrexone hydrochloride (NTX), a water-soluble low-molecular-weight drug was chosen as the model drug and the in situ gels were also prepared and studied comparatively. RESULTS: Slow-release characteristics were observed in vitro with in situ gels of LXT-101 and NTX. The release profiles and the mechanisms were different manifested by that NTX was released from in situ gels faster and more completely than LXT-101. Otherwise, the release pattern of LXT-101 showed a biphasic mechanism, an initial Fickian diffusion followed by a combination of degradation and diffusion at a later stage. The results of pharmacokinetic study indicated that a sustained release behavior could be obtained with MRT0-t (30.34 ± 12.47) h for LXT-101 and MRT0-t (2.37 ± 0.876) h for NTX, about 10 and 4 times longer than those of aqueous solution respectively. The pharmacodynamics studies in vivo further showed that in situ gel formulations of LXT-101 could sustain efficacy 6 days compared with only 1 day for aqueous solutions. CONCLUSION: The results of release behavior in vitro and in vivo indicated that in situ gels with copolymer 1115A could be served as carriers for delay-released drug delivery systems and might be more suitable for polypeptide drugs compared to low-molecular-weight hydrophilic drugs.

Anti-inflammatory activity of chitosan nanoparticles carrying NF-κB/p65 antisense oligonucleotide in RAW264.7 macropghage stimulated by lipopolysaccharide.

The purpose of this present study is to prepare NF-κB/p65 antisense oligonucleotide loaded chitosan nanoparticles (NPs) and evaluate their physicochemical characterization and antisense effects in RAW264.7 macrophages. Condensed nanoparticles with mean particle size of 128±16nm, average Zeta potential of 19.6±6.3mV and high entrapment efficiency (EE) of 98.6±0.11% were formed between NF-κB/p65 antisense gene (NAG) and chitosan by complex coacervation method. Trypan blue staining and MTT tests showed that NAG chitosan NPs had no toxic effect on RAW264.7 macrophages when the dose was no more than 20µg/mL. Confocal microscopy images showed that NAG chitosan NPs were capable to deliver NAG into cytoplasm of RAW264.7 macrophages and finally into nucleus. Real-time PCR tests verified that NAG chitosan NPs could significantly decrease the mRNA expression level of NF-κB/p65 and inflammatory cytokines including TNF-ɑ, IL-1 and IL-6. Accordingly, western blot study showed that NAG NPs uptaken in the cells could efficiently reversed the expression of NF-κB/p65 protein induced by LPS. At last, downstream release level of inflammatory factors including TNF-ɑ, IL-1 and IL-6 in LPS stimulated RAW264.7 macrophages was significantly decreased after treated by NAG chitosan NPs. It could be concluded that chitosan NPs were excellent delivery vectors to ferry the NAG into the cytoplasm and nucleus of macrophages. The NAG chitosan NPs might be a novel therapeutic apparatus for the treatment of LPS induced sepsis by inhibiting NF-κB-related pro-inflammatory cytokines secretion.

Effect of composite SiO2@AuNPs on wound healing: in vitro and vivo studies.

Recently gold nanomaterials have been widely applied in the biomedical field, but their biosafety is still controversial. We immobilized small gold nanoparticles (AuNPs) on a large silica substrate to form silica-gold core-shell materials (SiO2@AuNPs) via classical seed-mediated growth. In vitro, 500 nm-SiO2@AuNPs could promote the proliferation of mouse embryonic fibroblast cells (NIH/3T3). The results of transmission electron microscope (TEM) showed that the vast majority of particles did not enter cells and that the morphology of microtubules experienced no change as observed in the confocal microscope images. The mechanism may be that the large silica substrate kept AuNPs outside the cells and the nano-size concavo-convex gold shell facilitated to cell adhesion, resulting in the proliferation. In vivo, a cutaneous full-thickness excisional wound rat model was applied to assess the healing efficiency of 500 nm-SiO2@AuNPs. The results indicated that SiO2@AuNPs could promote wound healing, which was potentially related to the anti-inflammatory and antioxidation of AuNPs. The pathological finding showed that the healing levels of SiO2@AuNPs were significantly better than those of the control groups. Our study may provide insight into the application of silica-gold core-shell materials in the treatment of cutaneous wounds.

Dissolution evaluation in vitro and bioavailability in vivo of self-microemulsifying drug delivery systems for pH-sensitive drug loratadine.

The aim of this study was to improve the oral absorption of loratadine, a pH-sensitive drug, by self-microemulsifying drug delivery systems (SMEDDSs). The optimal SMEDDS was analysed and evaluated after emulsification in distilled water with diameter of 26.57 ± 0.71 nm and zeta potential of -30.5 ± 4.5 mV. Dissolution experiments in vitro were carried out in different released media of pH values and the SMEDDS formulations were able to release loratadine completely in different media while market tablets just performed similarly in the media of pH 1.2. Furthermore, the oral bioavailability and the pharmacokinetic behaviour of loratadine formulations in vivo were studied after a single dose of 1 mg/kg loratadine in beagle dogs. The SMEDDS formulations displayed higher Cmax and AUC, approximately 9 and 5 times increase than those of market tablets (p < 0.01) respectively. These results demonstrated that SMEDDS formulations had significantly increased the oral absorption of loratadine in beagle dogs.

Oil-based formulation as a sustained-released injection for a novel synthetic peptide.

In this study, sustained-release of GnRH antagonist peptide LXT-101 was realized through oil formulation, and their releasing characteristics in vitro and in vivo were investigated. In this formulation, the static interaction between cationic charged peptide LXT-101 and the negative charged phospholipid led to the formation of the phospholipid-peptide complex, by which LXT-101 was completely dissolved in oils. This formulation was prepared by mixing an aqueous solution of LXT-101 and empty SUV (small unilamellar liposomes) containing EPC (phosphatidylcholine) and DPPG (1, 2-dipalmitog-sn-glycero-3- phosphoglycerol) at an appropriate ratio, the mixture was subsequently lyophilized, and the resultant was dissolved in the oil to form a clear oily solution containing solubilized peptide LXT-101. With atomic force microscopy combined with Langmuir-Blodgett technology, the morphology of the particles in the oily solution were examined to be oval-shaped and the mean particle size was 150 nm in diameter. In pure water at 37°C, about 70~90 % of LXT-101 was released slowly from the oily formulation over 7 days. An effective sustained suppression of testosterone in beagle dogs could be achieved over a period of seven days with this LXT-101 oily formulation, by i.m. at a dose of 0.2 mg/kg (2 mg/ml). This formulation dramatically improved the bioactivity of LXT-101 compared to its aqueous solution. It was also found that when the concentration of peptide LXT-101 was up to or over 10 mg/ml in aqueous solution, there was no significant difference between the oily formulation and aqueous solution. This fact meant that LXT-101 itself could conduct sustained release in vivo by self-assembly of nanofibers.