Construction and in vitro/in vivo evaluation of menantine hydrochloride oral liquid sustained-release drug delivery system.

OBJECTIVE: The purpose of the present study was to formulate a menantine hydrochloride (MH) sustained-release suspension. METHODS: Menantine hydrochloride drug resin complex (MH-DRC) was prepared with strong acid cation exchange resin as carrier using water bath method. The MH-DRC was characterized using scanning electron microscopy, X-ray diffraction and infrared spectroscopy. The MH-coated microcapsule (MH-CM) with optimized formulation was further dispersed in a suitable medium to obtain a sustained-release suspension. The rats were given both the MH sustained-release suspension and the commercial MH sustained-release capsule by intragastric administration. The plasma concentration-time curves and related pharmacokinetic parameters were also investigated using a non-atrioventricular model. RESULTS: MH and ion-exchange resin were ionically bonded. AmberliteIRP®69 had a higher affinity for MH at the initial concentration of 5 mg·mL-1 and a reaction temperature of 25.0 ± 0.5 °C. In vitro drug release profile showed that both the drug resin complex and the coated microcapsules had a certain level of sustained-release effect. The t1/2 of MH sustained-release suspension was extended from 68.44 h to 72.79 h with the peak blood concentration being decreased to 3.56 µg·mL-1 and the Tmax extended to 12 h compared with the commercial MH sustained-release capsule. The concentration-time curve of the self-made MH sustained-release suspension was flattened and the average relative bioavailability (Fr) was 116.65% compared with the commercial MH sustained-release capsules. CONCLUSIONS: The findings showed that the MH sustained-release suspension was successfully formulated with acceptable pharmacokinetic indices for effective treatment of Alzheimer's disease.

Production and evaluation of monovalent anti-snake immunoglobulins from chicken egg yolk using Ghanaian puff adder (Bitis arietans) Venom: Isolation, purification, and neutralization efficacy.

Snakebites are rampant in Ghana, especially among the farmers, herdsmen, military recruits, hunters, and rural dwellers, and the antisnake venoms (ASV) use to treat these bites are not locally produced but rather imported, which come with a high cost, lack of constant supply and low specificity. The study was therefore aimed at isolating, purifying, and evaluating the efficacy of monovalent ASV from chicken egg yolk using puff adder (Bitis arietans) venom from Ghana. The major pathophysiological properties of the venom and the efficacy of the locally produced ASV were evaluated. The results showed that the snake venom (LD50 of 0.85 mg/kg body weight) had anticoagulant, haemorrhagic, and edematic activities in mice which were effectively neutralized using the purified egg yolk immunoglobulin Y (IgY), with two distinct molecular weight bands (∼70 and 25 kDa). The cross-neutralization studies also showed that the venom/IgY mixture (2.55 mg/kg body weight: 90 mg/kg body weight) offered 100% protection to the animals with ED50 of IgY being 22.66 mg/kg body weight. However, the applied dose (11.36 mg/kg body weight) of the available polyvalent ASV offered 25% protection compared with the 62% protection of the IgY at the same dose. The findings showed successful isolation and purification of a Ghanaian monovalent ASV with a better neutralization efficacy compared with the clinically available polyvalent drug.

Preparation and evaluation of sustained release pirfenidone-loaded microsphere dry powder inhalation for treatment of idiopathic pulmonary fibrosis.

Pirfenidone (PFND) is a recommended oral drug used to treat idiopathic pulmonary fibrosis, but have low bioavailability and high hepatotoxicity. The study, therefore, seeks to improve the therapeutic activities of the drug via increased bioavailability and reduced associated side effects by developing a novel drug delivery system. The electrostatic spray technology was used to prepare a sustained release pirfenidone-loaded microsphere dry powder inhalation with PEG-modified chitosan (PFND-mPEG-CS-MS). The entrapment efficiency, drug loading, and in vitro cumulative drug release rate (at 24 h and with a sustained release effect) of PFND-mPEG-CS-MS were 77.35±3.01%, 11.45±0.64%, and 90.4%, respectively. The Carr's index of PFND-mPEG-CS-MS powder was 17.074±2.163% with a theoretical mass median aerodynamic diameter (MMADt) of 0.99±0.07 µm, and a moisture absorption weight gain rate (Rw) of 4.61±0.72%. The emptying rate, pulmonary deposition rate (fine particle fraction) and actual mass median aerodynamic diameter (MMADa) were 90%∼95%, 48.72±7.04% and 3.10±0.16 µm, respectively. MTT bioassay showed that mPEG-CS-MS (200 µg/mL) had good biocompatibility (RGR = 90.25%) and PFND-mPEG-CS-MS (200 µg/mL) had significant inhibitory activity (RGR = 49.82%) on fibroblast growth. The pharmacokinetic data revealed that the t1/2 (5.02 h) and MRT (10.66 h) of PFND-mPEG-CS-MS were prolonged compared with the free PFND (t1/2, 1.67 h; MRT, 2.71 h). The pharmacodynamic results also showed that the formulated-drug group had slight pathological changes, lower lung hydroxyproline content, and reduced hepatotoxicity compared with the free-drug group. The PFND-mPEG-CS-MS further significantly down-regulated TGF-ß cytokines, Collagen I, and α-SMA protein expression levels compared with the free drug. The findings indicated that the PFND-mPEG-CS-MS had a good sustained release effect, enhanced bioavailability, decreased toxicity, and increased anti-fibrotic activities.

Construction and Evaluation of Traceable rhES-QDs-M-MS Protein Delivery System: Sustained-Release Properties, Targeted Effect, and Antitumor Activity.

Recombinant human endostatin (rhES) is a protein drug with poor stability and short in vivo circulation time. The present study was therefore aimed at developing sustained-release lung targeted microspheres drug delivery system and evaluating its targeting efficiency using in vivo imaging techniques with quantum dots (QDs) as the imaging material. The oil-soluble QDs were coated with amphiphilic polymers to obtain a polymer-quantum dots micelle (QDs-M) with the potential to stably disperse in water. The rhES and QDs-M were combined using covalent bonds. The rhES-QDs-M microspheres (rhES-QDs-M-MS) were prepared using electrostatic spray technology and also evaluated via in vivo imaging techniques. The pharmacodynamics was further studied in mice. The rhES-QDs-M-MS (4-8 µm) were stable in an aqueous medium with good optical properties. The in vitro studies showed that the rhES-QDs-M-MS had sustained release which was maintained for at least 15 days (cumulative release >80%) without any burst release. The rhES-QDs-M-MS had a very high safety profile and also effectively inhibited the in vitro proliferation of human umbilical vein endothelial cells by about 70%. The pharmacokinetic results showed that the rhES could still be detected at 72 h in the experimental group which meant that the rhES-QDs-M-MS had a significant sustained-release effect. The rhES-QDs-M-MS had a better lung targeting effect and higher antitumor activity compared with the rhES. The traceable rhES-QDs-M-MS served as a promising drug delivery system for the poorly stable rhES proteins and significantly increased its lung-targeted effect, sustained-release properties, and antitumor activities.

Preparation and Evaluation of rhINF-α-2b Sodium Hyaluronate Cross-Linked Porous Microspheres: Characterization, Sustained-Release Properties, and Antitumor Activity.

Recombinant human interferon α-2b (rhINF-α-2b), like most proteins, has several shortcomings such as relatively short half-life, low therapeutic index, high circulating drug fluctuations, and rapid degradation which could hinder its effective delivery. Novel electrostatic spray and ion exchange drug-loading techniques were combined to formulate rhINF-α-2b sodium hyaluronate cross-linked porous sustained-release microspheres (rhINF-α-2b-SHCPM), a protein delivery system. The different properties of rhINF-α-2b-SHCPM including the physicochemical nature, in vitro release behavior, and antitumor activity were evaluated. The loading rate (10.31 ± 0.94%) and encapsulation efficiency (89.09 ± 2.37%) of rhINF-α-2b-SHCPM produced acceptable values. The in vitro cumulative release rate of rhINF-α-2b-SHCPM within 24 h was also 86.26 ± 2.11% with a much better sustained release effect. Thus, the half-life (10.763 h) and retention time (14.067 h) of rhIFNα-2b-SHCPM were significantly prolonged with enhanced bioavailability (43,198.387 ng/L*h) and decreased peak concentration (15,266.4 ngL-1) compared with the free rhIFNα-2b protein (0.912 h, 0.952 h, 34,749.048 ng/L*h, and 48,870.2 ngL-1, respectively). The in vitro anti-proliferative activity and in vivo tumor inhibitory rate of rhIFNα-2b-SHCPM also increased by 90 and 55.86%, respectively, compared with the free rhIFNα-2b solution. The findings significantly supported a well-developed protein delivery system with improved sustained release, acceptable bioavailability, and increased antitumor activities. Graphical Abstract.

Preparation and in vitro/in vivo evaluation of a clonidine hydrochloride drug-resin suspension as a sustained-release formulation.

OBJECTIVE: The purpose of the present study was to prepare a clonidine hydrochloride (CH) sustained-release suspension. METHODS: The processes involved in the drug formulation included drug loading, impregnating, and suspension preparation. Clonidine hydrochloride drug-resin complexes (CH-DRC) were prepared using the bath method and the CH-DRC impregnated before the microencapsulation process. Based on the bottom spray fluidized bed coating method, the CH microencapsulated drug-resin complexes (CH-MC) were also prepared using Surelease® (the suspension of ethyl cellulose aqueous dispersion) as the coating material. The effects of coating (process/formulation) on the in vitro release of coating microcapsule were evaluated via single factor investigation and orthogonal design optimization. The CH-MC with optimized formulation was further dispersed in a suitable medium to obtain a sustained-release suspension. Rats were given commercial CH ordinary tablets and the CH sustained-release suspension via intragastric administration. The plasma concentration-time curve and related pharmacokinetic parameters were investigated using the non-compartment model. RESULTS: The Tmax of the CH sustained-release suspension was delayed from 2 h to 5 h compared with the CH ordinary tablets. Similarly, the Cmax was reduced from 32.138 µg·mL-1 to 18.150 µg·mL-1 with the concentration-time curve being more gentle compared with the commercially CH ordinary tablets. After oral administration, the relative bioavailability of CH sustained-release suspension (AUC0-24 of 137.703 µg·h·mL-1) to its CH ordinary tablets (AUC0-24 of 123.337 µg·h·mL-1) was 111.65%. CONCLUSIONS: The findings showed that the CH sustained-release suspension for oral administration was successfully formulated.

Novel cuminaldehyde self-emulsified nanoemulsion for enhanced antihepatotoxicity in carbon tetrachloride-treated mice.

OBJECTIVES: Cuminaldehyde self-emulsified nanoemulsion (CuA-SEN) was prepared and optimised to improve its oral bioavailability and antihepatotoxicity. METHODS: Cuminaldehyde self-emulsified nanoemulsion was developed through the self-nanoemulsification method using Box-Behnken Design (BBD) tool while appropriate physicochemical indices were evaluated. The optimised CuA-SEN was characterised via droplet size (DS), morphology, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, in-vitro release, and pharmacokinetic studies while its antihepatotoxicity was evaluated. KEY FINDINGS: Cuminaldehyde self-emulsified nanoemulsion with acceptable characteristics (mean DS-48.83 ± 1.06 nm; PDI-0.232 ± 0.140; ZP-29.92 ± 1.66 mV; EE-91.51 ± 0.44%; and drug-loading capacity (DL)-9.77 ± 0.75%) was formulated. In-vitro drug release of CuA-SEN significantly increased with an oral relative bioavailability of 171.02%. Oral administration of CuA-SEN to CCl4 -induced hepatotoxicity mice markedly increased the levels of superoxide dismutase, glutathione and catalase in serum. Also, CuA-SEN reduced the levels of tumour necrosis factor-alpha and interleukin-6 in both serum and liver tissues while aspartate aminotransferase, alanine aminotransferase and malonaldehyde levels were significantly decreased. CONCLUSIONS: These findings showed that the improved bioavailability of cuminaldehyde via SEN provided an effective approach for enhancing antioxidation, anti-inflammation and antihepatotoxicity of the drug.

Anti-hyperuricemic property of 6-shogaol via self-micro emulsifying drug delivery system in model rats: formulation design, in vitro and in vivo evaluation.

The prevalence of hyperuricemia is relatively high worldwide, and a great number of patients are suffering from its complications. 6-shogaol, an alkylphenol compound purified from the root of ginger (Zingiber officinale Roscoe), has been proved to possess diverse pharmacological activities. However, its poor aqueous solubility usually leads to low bioavailability, and further clinical applications will be greatly discounted. The current study aimed to formulate a 6-shogaol-loaded-Self Microemulsifying Drug Delivery System (SMEDDS) to amend low aqueous solubility and bioavailability orally, as well as, potentiate the hyperuricemic activity of the 6-shogaol. SMEDDS was developed with central composite design established on a two system components viz., 18.62% W/W ethyl oleate (oil phase) and ratio of tween 80 (surfactant) to PEG 400 (co-surfactant) (1.73:1, W/W). Based on quadratic model, the navigation of the design space could generate spherically-shaped and homogenous droplets with respective mean particle diameter, polydispersity and of 20.00 ± 0.26 nm and 0.18 ± 0.02. The 6-shogaol-SMEDDS showed significant elevation of cumulative release compared with the free 6-shogaol and more importantly a 571.18% increment in the relative oral bioavailability of the drug. The predominant accumulation of 6-shogaol-SMEDDS in the liver suggested hepatic-targeting potentiality of the drug. Oral administration of 6-shogaol-SMEDDS in hyperuricemic rats also significantly decreased uric acid level and xanthine oxidase activity. Histological studies confirmed formulation groups indeed could provide better protection of kidney than free drug groups. Collectively, these findings indicated that the SMEDDS hold much promise in enhancing the oral delivery and therapeutic efficacy of 6-shogaol.

Self-microemulsifying Drug Delivery System for Improved Oral Delivery of Limonene: Preparation, Characterization, in vitro and in vivo Evaluation.

The current investigation aimed at formulating self-microemulsifying drug delivery system (SMEDDS) to ameliorate oral bioavailability of a hydrophobic functional ingredient, limonene. Solubility test, compatibility test, and pseudo-ternary phase diagrams (PTPD) were adopted to screen the optimal compositions of limonene-SMEDDS (L-SMEDDS). The characteristics of this system assessed in vitro, mainly included determination of particle size distribution, observation of morphology via transmission electron microscopy (TEM), testing of drug release in different dissolution media, and evaluation of stability. The oral bioavailability study in vivo of the formulated limonene was performed in rats with the free limonene as the reference. Compared with the free limonene, the distribution study of L-SMEDDS was conducted in Kunming mice after oral administration. The optimized SMEDDS (ethyl oleate, 14.2%; Cremophor EL, 28.6%; isopropanol, 28.6%; and loaded limonene, 28.6%) under the TEM (about 100 nm) was spherical with no significant variations in size/appearance for 30 days at 4, 25, and 60°C. In comparison with free limonene, higher than 89.0% of limonene was released from SMEDDS within 10 min in different dissolution media. An in vivo study showed a 3.71-fold improved oral bioavailability of the formulated limonene compared to the free limonene. The tissue distribution results showed that limonene predominantly accumulated in the various tissues for the L-SMEDDS compared with the free limonene. Hence, L-SMEDDS could remarkably improve the concentration of limonene in the various organs. These findings hinted that the oral bioavailability of limonene could be improved via an effectual delivery system like SMEDDS.

Preparation, optimization, and pharmacokinetic study of nanoliposomes loaded with triacylglycerol-bound punicic acid for increased antihepatotoxic activity.

Punicic acid of pomegranate oil (PAP) has gained heightened interest due to several health benefits, such as anticarcinogenic, antidiabetic, and antiatherosclerotic properties. However, these bioactivities have been hampered by chemical instability, poor water solubility, rapid metabolism, and low bioavailability of PAP. Therefore, this study was aimed at optimizing the liposomal formulation of Triacylglycerol-bound punicic acid with its regioisomers (TPAR) for improved oral bioavailability and increased hepatoprotection through antioxidation and anti-inflammation. Herein, the optimized TPAR nanoliposome (TPAR-NL) was developed using thin-film dispersion method and subsequently characterized with appropriate indices. The optimized TPAR-NL produced fairly stable spherical nanoparticles (˂ 200 nm) with encapsulation efficiency (%EE) of 85.77%, as well as enhanced in vitro release and improved oral bioavailability. The TPAR-NL exhibited profound antihepatotoxic effect in mice pretreated with carbon tetrachloride (CCl4 ) via reduction of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels compared with free TPAR. The TPAR-loaded liposome also significantly reduced oxidative stress by increasing superoxide dismutase and glutathione levels while lowering malonaldehyde concentration compared with the free TPAR. The TPAR-LNF further exhibited remarkable anti-inflammatory activity compared with the free drug via inhibition of interleukin-6 and tumor necrosis factor-alpha generation. Thus, the developed nanoliposomes potentiated the antihepatotoxic activity of TPAR via antioxidation and anti-inflammation.

Enhanced Solubility and Bioavailability of Naringenin via Liposomal Nanoformulation: Preparation and In Vitro and In Vivo Evaluations.

This study was aimed at preparing orally administered naringenin-loaded liposome for pharmacokinetic and tissue distribution studies in animal models. The liposomal system, consisting of phospholipid, cholesterol, sodium cholate, and isopropyl myristate, was prepared using the thin-film hydration method. Physicochemical characterization of naringenin-loaded liposome such as particle size, zeta potential, and encapsulation efficiency produced 70.53 ± 1.71 nm, -37.4 ± 7.3 mV, and 72.2 ± 0.8%, respectively. The in vitro release profile of naringenin from the formulation in three different media (HCl solution, pH 1.2; acetate buffer solution, pH 4.5; phosphate buffer solution, pH 6.8) was significantly higher than the free drug. The in vivo studies also revealed an increase in AUC of the naringenin-loaded liposome from 16648.48 to 223754.0 ng·mL-1 h as compared with the free naringenin. Thus, approximately 13.44-fold increase in relative bioavailability was observed in mice after oral administration. The tissue distribution further showed that the formulation was very predominant in the liver. These findings therefore indicated that the liposomal formulation significantly improved the solubility and oral bioavailability of naringenin, thus leading to wider clinical applications.

Tissue distribution and enhanced in vivo anti-hyperlipidemic-antioxidant effects of perillaldehyde-loaded liposomal nanoformulation against Poloxamer 407-induced hyperlipidemia.

An optimized perillaldehyde-loaded liposomal nanoformulation (PAH-LNF) was successfully applied to improve the pharmacological effect of perillaldehyde (PAH) in poloxamer 407-induced hyperlipidemia. Oral administration of PAH-LNF (240mg/kg per body weight) in rats significantly enhanced solubility and relative bioavailability (270.7%) compared to the free PAH with about 2.7-, 1.5-, 1.3-, 1.3- and 1.5-fold increase in AUC, T1/2, MRT, Cmax and Tmax, respectively. Tissue distribution study also revealed the accumulation of PAH in the liver, lungs, spleen, kidney, brain and heart in order of decreasing affinity. Moreover, a significant decrease in serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) with simultaneous increase in high-density lipoprotein cholesterol (HDL-C) level was observed in the chemically-induced hyperlipidemic mice which further confirmed PAH's anti-hyperlipidemic properties. Additionally, PAH-LNF also significantly increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) with a concurrent decrease in malondialdehyde (MDA) to affirm the antioxidant and hepatoprotective effects of PAH. Thus, liposomal nanoformulation promises to be a useful drug delivery system for the development of PAH.

Ergosterol-loaded poly(lactide-co-glycolide) nanoparticles with enhanced in vitro antitumor activity and oral bioavailability.

AIM: Ergosterol is a plant sterol with anti-tumor and anti-angiogenic activities, but is poorly soluble. In this study, we attempted to enhance its anti-tumor action and oral bioavailability via poly(lactide-co-glycolide) (PLGA) nanoparticle encapsulation. METHODS: Ergosterol-loaded PLGA nanoparticles (NPs/Erg) were prepared using the emulsion/solvent evaporation technique. Their physicochemical properties were characterized, and their cytotoxicity against human cancer cell lines was evaluated with MTT assay. The pharmacokinetics and tissue distribution of NPs/Erg were investigated in rats and mice, respectively. RESULTS: NPs/Erg were spherical in shape with a particle size of 156.9±4.8 nm and a Zeta potential of -19.27±1.13 mV, and had acceptable encapsulation efficiency and loading capacity. NPs/Erg exerted much stronger cytotoxicity against human cancer cells than the free ergosterol, and showed significantly reduced IC50 values (14.69±0.48 µg/mL in glioma U251 cells; 9.43±0.52 µg/mL in breast cancer MCF-7 cells; 4.70±0.41 µg/mL in hepatoma HepG2 cells). After oral administration of a single dose in rats, NPs/Erg displayed a prolonged plasma circulation with a 4.9-fold increase of oral bioavailability compared with the free ergosterol. After mice received NPs/Erg, the ergosterol in NPs/Erg was rapidly distributed in stomach, kidneys, liver, brain, spleen, and virtually non-existent in heart and lungs. The presence of NPs/Erg in brain was particularly improved compared with the free ergosterol. CONCLUSION: The PLGA nanoparticles serve as a promising carrier for the poorly soluble ergosterol and significantly improve its bioavailability, biodistribution and in vitro anti-tumor activities.

Segetoside I, a plant-derived bisdesmosidic saponin, induces apoptosis in human hepatoma cells in vitro and inhibits tumor growth in vivo.

Segetoside I is a plant-derived bisdesmosidic saponin from Vaccaria segetalis (Neck) with reported anticancer activities. This development has raised an interest in the therapeutic potential of segetoside I. Here, we report the in vitro and in vivo antitumor activities of segetoside I against some selected cancer cell lines (HepG2, human hepatoma; H22, mouse hepatoma; MCF-7, breast cancer; U251, gliocoma; BGC, HGC & SGC, gastric cancinoma; Lovo-1,colon cancer). MTT bioassay analysis showed that HepG2 cells were the most sensitive to segetoside I compared with other cancer cell lines, with lower toxicity in healthy mouse embryonic fibroblast cells. Segetoside I pretreatment of HepG2 resulted in apoptotic induction, dose-dependent DNA fragmentation, inhibition of cell migration, up-regulation of Bax and down-regulation of Bcl-2, which indicated that an apoptotic signaling event could have been initiated. The segetoside I also suppressed hepato-tumour growth in mice with virtually no cytotoxicity and prolonged animal survival, making it a strong oncology drug agent. These findings showed that segetoside I exhibited its antitumor activity via apoptotic induction and significantly support the possible application of the antitumor agent as a potential chemotherapeutic candidate worthy of further investigations.

Preparation, characterization and pharmacokinetic studies of linalool-loaded nanostructured lipid carriers.

Context Linalool (LL) is associated with numerous pharmacological activities. However, its poor solubility usually results in poor bioavailability, and further limited its applications. Objective To reduce volatilization and improve bioavailability of LL, linalool-loaded nanostructured lipid carriers (LL-NLCs) were prepared. Materials and methods LL-NLCs were prepared using high-pressure homogenization method and optimized via response surface methodology-central composite design, followed by characterization, including particle size (PS), zeta potential (ZP), transmission electron microscope (TEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and in vitro release study. Rats were administered 300 mg × kg (-) (1) LL with each preparation (LL-NLCs or LL) via oral gavage. Results LL-NLCs had a PS of 52.72 nm with polydispersity index of 0.172, and ZP of -16.0 mV. The encapsulation efficiency and drug loading gave 79.563 and 7.555%, respectively. The cumulative release of LL from free LL reached 51.414% at 180 min, while LL from LL-NLCs was 15.564%. All the pharmacokinetics parameters of LL-NLCs were better than those of LL, including Cmax (from 1915.45 to 2182.45 ng × mL (-) (1)), AUC0-t (from 76003.40 to 298948.46 ng × min × mL (-) (1)) and relative bioavailability (393.34%). The t1/2, MRT and tmax of LL-NLCs (110.50, 146.66 and 60 min) were also longer than that of LL (44.72, 45.66 and 40 min). Discussion and conclusion LL-NLCs were for the first time prepared and its oral administration in rats thoroughly investigated. LL-NLCs exhibited sustained release effect and increased absorption of LL. Therefore, these findings might provide a potential possibility for clinical application of LL.

Hypolipidemic potential of perillaldehyde-loaded self-nanoemulsifying delivery system in high-fat diet induced hyperlipidemic mice: Formulation, in vitro and in vivo evaluation.

This study reports the hypolipidemic effects of perillaldehyde-loaded self-nanoemulsifying delivery system (PAH-SNEDS) developed with D-optimal experimental design based on a three component system: 40% w/w drug-oil phase, X1 (a mixture of perillaldehyde-isopropyl myristate/medium chain triglyceride, 1:1, w/w); 48% surfactant, X2 (Kolliphor EL); and 12% co-surfactant, X3 (PEG 200). The design space was navigated using a linear model to produce spherical and homogenous droplets which were observed under TEM, with mean size, polydispersity index (PDI) and zeta potential of 32.8 ± 0.1 nm, 0.270 ± 0.029 and -10.14 ± 0.66 mV, respectively. PAH-SNEDS demonstrated significant increase in dissolution in vitro compared to the free PAH, and further yielded an oral relative bioavailability of about 206.18% in vivo which suggested a promising formulation design for potential liquid bioactive compounds. Oral administration of PAH-SNEDS (240 mg/kg per body weight) in high-fat induced hyperlipidemia in mice, also significantly decreased serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C) level. The improved bioavailability and functional application of PAH via SNEDDS suggested a suitable approach to promote hypolipidemic effect of the drug. Perillaldehyde, therefore, promises to be a useful bioactive compound to prevent high-fat diet induced hyperlipidemia.

Enhanced oral bioavailability and in vivo antioxidant activity of chlorogenic acid via liposomal formulation.

In the present study, a formulation system consisting of cholesterol and phosphatidyl choline was used to prepare an effective chlorogenic acid-loaded liposome (CAL) with an improved oral bioavailability and an increased antioxidant activity. The developed liposomal formulation produced regular, spherical and multilamellar-shaped distribution nanoparticles. The pharmacokinetic analysis of CAL compared with chlorogenic acid (CA), showed a higher value of Cmax(6.42 ± 1.49 min versus 3.97 ± 0.39 min) and a delayed Tmax(15 min versus 10 min), with 1.29-fold increase in relative oral bioavailability. The tissue distribution in mice also demonstrated that CAL predominantly accumulated in the liver which indicated hepatic targeting potential of the drug. The increased activities of antioxidant enzymes (Total Superoxide Dismutase (T-SOD) and Glutathione Peroxidase (GSH-Px)) and total antioxidant capacity (T-AOC), in addition to decreased level of malondialdehyde (MDA) in CCl4-induced hepatotoxicity study further revealed that CAL exhibited significant hepatoprotective and antioxidant effects. Collectively, these findings present a liposomal formulation with significantly improved oral bioavailability and an increased in vivo antioxidant activity of CA.

Preparation, characterization, and pharmacokinetics study of capsaicin via hydroxypropyl-beta-cyclodextrin encapsulation.

CONTEXT: Capsaicin (CAP) is an effective drug in the treatment of pain and cancer. However, its practical administration has been limited due to poor aqueous solubility and bioavailability, as well as strong gastrointestinal irritation. OBJECTIVE: The objective of this study is to improve the solubility and oral bioavailability of CAP by reducing irritation via hydroxypropyl-ß-cyclodextrin (HP-ß-CD) inclusion complex formulation, in vitro and in vivo analysis. MATERIALS AND METHODS: The complex (CAP-HP-ß-CD) was developed via the magnetic stirring method and characterized using ultraviolet (UV) absorption spectrometry, infrared radiation (IR) spectroscopy, and differential scanning calorimetry (DSC). Rats were treated with CAP (90 mg × kg(-1)) or CAP-HP-ß-CD (corresponding to 90 mg × kg(-1) CAP) by gavage, and all the plasma samples were analyzed with high performance liquid chromatography (HPLC). RESULTS: The results of UV, IR, and DSC showed that an acceptable CAP-HP-ß-CD (encapsulation efficiency, 75.83%; drug loading, 7.44%) was formulated. In vitro release study of CAP-HP-ß-CD revealed that the cumulative release of CAP from HP-ß-CD encapsulation was obviously enhanced (above 80% increases). Similarly, the in vivo pharmacokinetics parameters also increased, Cmax (from 737.94 to 1117.57 ng × mL(-1)), AUC0- (from 5285.9 to 7409.8 ng × h × mL(-1)) or relative bioavailability (139.38%). The gastric irritation bioassay further showed that the CAP-HP-ß-CD was far better than free CAP. DISCUSSION AND CONCLUSION: CAP exhibited significant aqueous solubility and oral bioavailability, as well as minimal irritation effect after forming inclusion complex with HP-ß-CD. Therefore, these findings could provide an equally important alternative option for the clinical use of CAP.

Improved oral bioavailability of capsaicin via liposomal nanoformulation: preparation, in vitro drug release and pharmacokinetics in rats.

This study innovatively prepared an effective capsaicin-loaded liposome, a nanoformulation with fewer irritants, for oral administration. The in vitro and in vivo properties of the liposomal encapsulation were investigated and the potential possibility of oral administration evaluated. The liposomal agent composed of phospholipid, cholesterol, sodium cholate and isopropyl myristate was prepared using film-dispersion method. A level A in vitro-in vivo correlation (IVIVC) was established for the first time, which demonstrated an excellent IVIVC of both formulated and free capsaicin in oral administration. Physicochemical characterizations including mean particle size, zeta (ζ) potential and average encapsulation efficiency of capsaicin-loaded liposome were found to be 52.2 ± 1.3 nm, -41.5 ± 2.71 mv and 81.9 ± 2.43 %, respectively. In vivo, liposomal encapsulation allowed a 3.34-fold increase in relative bioavailability compared to free capsaicin. The gastric mucosa irritation studies indicated that the liposomal system was a safe carrier for oral administration. These results support the fact that capsaicin, an effective drug for the treatment of neuropathic pain, could be encapsulated in liposome for improved oral bioavailability. The excellent IVIVC of capsaicin-loaded liposome could also be a promising tool in liposomal formulation development with an added advantage of reduced animal testing.

In vitro and in vivo evaluation of capsaicin-loaded microemulsion for enhanced oral bioavailability.

BACKGROUND: Capsaicin, as a food additive, has attracted worldwide concern owing to its pungency and multiple pharmacological effects. However, poor water solubility and low bioavailability have limited its application. This study aims to develop a capsaicin-loaded microemulsion to enhance the oral bioavailability of the anti-neuropathic-pain component, capsaicin, which is poorly water soluble. RESULTS: In this study, the microemulsion consisting of Cremophor EL, ethanol, medium-chain triglycerides (oil phase) and water (external phase) was prepared and characterized (particle size, morphology, stability and encapsulation efficiency). The gastric mucosa irritation test of formulated capsaicin was performed in rats to evaluate its oral feasibility, followed by the pharmacokinetic study in vivo. Under these conditions, the encapsulated capsaicin revealed a faster capsaicin release in vitro coupled with a greater absorption in vivo when compared to the free capsaicin. The oral bioavailability of the formulated capsaicin-loaded microemulsions was 2.64-fold faster than that of free capsaicin. No significant irritation was observed on the mucosa from the pathological section of capsaicin-loaded microemulsion treated stomach. CONCLUSION: These results indicate that the developed microemulsion represents a safe and orally effective carrier for poorly soluble substances. The formulation could be used for clinical trials and expand the application of capsaicin.