Enhanced oral delivery of hesperidin-loaded sulfobutylether-ß-cyclodextrin/chitosan nanoparticles for augmenting its hypoglycemic activity: in vitro-in vivo assessment study.

Hesperidin (Hsd), a bioactive phytomedicine, experienced an antidiabetic activity versus both Type 1 and Type 2 Diabetes mellitus. However, its intrinsic poor solubility and bioavailability is a key challenging obstacle reflecting its oral delivery. From such perspective, the purpose of the current study was to prepare and evaluate Hsd-loaded sulfobutylether-ß-cyclodextrin/chitosan nanoparticles (Hsd/CD/CS NPs) for improving the hypoglycemic activity of the orally administered Hsd. Hsd was first complexed with sulfobutylether-ß-cyclodextrin (SBE-ß-CD) and the complex (CX) was found to be formed with percent complexation efficiency and percent process efficiency of 50.53 ± 1.46 and 84.52 ± 3.16%, respectively. Also, solid state characterization of the complex ensured the inclusion of Hsd inside the cavity of SBE-ß-CD. Then, Hsd/CD/CS NPs were prepared using the ionic gelation technique. The prepared NPs were fully characterized to select the most promising one (F1) with a homogenous particle size of 455.7 ± 9.04 nm, a positive zeta potential of + 32.28 ± 1.12 mV, and an entrapment efficiency of 77.46 ± 0.39%. The optimal formula (F1) was subjected to further investigation of in vitro release, ex vivo intestinal permeation, stability, cytotoxicity, and in vivo hypoglycemic activity. The results of the release and permeation studies of F1 manifested a modulated pattern between Hsd and CX. The preferential stability of F1 was observed at 4 ± 1 °C. Also, the biocompatibility of F1 with oral epithelial cell line (OEC) was retained up to a concentration of 100 µg/mL. After oral administration of F1, a noteworthy synergistic hypoglycemic effect was recorded with decreased blood glucose level until the end of the experiment. In conclusion, Hsd/CD/CS NPs could be regarded as a hopeful oral delivery system of Hsd with enhanced antidiabetic activity.

Formulation of lipid polymer hybrid nanoparticles of the phytochemical Fisetin and its in vivo assessment against severe acute pancreatitis.

Fisetin (FST) is a naturally occurring flavonol that has recently emerged as a bioactive phytochemical with an impressive array of biological activities. To the author knowledge, boosting the activity of FST against severe acute pancreatitis (SAP) through a nanostructured delivery system (Nanophytomedicine) has not been achieved before. Thereupon, FST-loaded lipid polymer hybrid nanoparticles (FST-loaded LPHNPs) were prepared through conjoined ultrasonication and double emulsion (w/o/w) techniques. Comprehensive in vitro and in vivo evaluations were conducted. The optimized nanoparticle formula displayed a high entrapment efficiency % of 61.76 ± 1.254%, high loading capacity % of 32.18 ± 0.734, low particle size of 125.39 ± 0.924 nm, low particle size distribution of 0.357 ± 0.012, high zeta potential of + 30.16 ± 1.416 mV, and high mucoadhesive strength of 35.64 ± 0.548%. In addition, it exhibited a sustained in vitro release pattern of FST. In the in vivo study, oral pre-treatment of FST-loaded LPHNPs protected against L-arginine induced SAP and multiple organ injuries in rats compared to both FST alone and plain LPHNPs, as well as the untreated group, proven by both biochemical studies, that included both amylase and lipase activities, and histochemical studies of pancreas, liver, kidney and lungs. Therefore, the study could conclude the potential efficacy of the novel phytopharmaceutical delivery system of FST as a prophylactic regimen for SAP and consequently, associated multiple organ injuries.

Novel Clove Essential Oil Nanoemulgel Tailored by Taguchi's Model and Scaffold-Based Nanofibers: Phytopharmaceuticals with Promising Potential as Cyclooxygenase-2 Inhibitors in External Inflammation.

PURPOSE: Clove essential oil is a phytochemical possessing a vast array of biological activities. Nevertheless, fabricating nano topical delivery systems targeted to augment the anti-inflammatory activity of the oil has not been investigated so far. Accordingly, in this study, controlled release nanoparticulate systems, namely nanoemulgel and nanofibers (NFs), of the oil were developed to achieve such goal. METHODS: The nanoemulsion was incorporated in the hydrogel matrix of mixed biopolymers - chitosan, guar gum and gum acacia - to formulate nanoemulsion-based nanoemulgel. Taguchi's model was adopted to evaluate the effect of independently controlled parameters, namely, the concentration of chitosan (X1), guar gum (X2), and gum acacia (X3) on different dependently measured parameters. Additionally, the nanoemulsion-based NFs were prepared by the electrospinning technique using polyvinyl alcohol (PVA) polymer. Extensive in vitro, ex vivo and in vivo evaluations of the aforementioned formulae were conducted. RESULTS: Both Fourier transform-infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) established the complete dispersion of the nanoemulsion in the polymeric matrices of the prepared nanoemulgel and NFs. The ex vivo skin permeation data of clove essential oil from the prepared formulations showed that NFs can sustain its penetration through the skin comparably with nanoemulgel. Topical treatment with NFs (once application) and nanoemulgel (twice application) evoked a marvelous in vivo anti-inflammatory activity against croton oil-induced mouse skin inflammation model when compared with pure clove essential oil along with relatively higher efficacy of medicated NFs than that of medicated nanoemulgel. Such prominent anti-inflammatory activity was affirmed by histopathological and immunohistochemical examinations. CONCLUSION: These results indicated that nanoemulsion-based nanoemulgel and nanoemulsion-based NFs could be introduced to the phytomedicine field as promising topical delivery systems for effective treatment of inflammatory diseases instead of nonsteroidal anti-inflammatory drugs that possess adverse effects.

Novel chitosan oligosaccharide-based nanoparticles for gastric mucosal administration of the phytochemical "apocynin".

Background: Apocynin (APO) is a bioactive phytochemical with prominent anti-inflammatory and anti-oxidant activities. Designing a nano-delivery system targeted to potentiate the gastric antiulcerogenic activity of APO has not been investigated yet. Chitosan oligosaccharide (COS) is a low molecular weight chitosan and its oral nanoparticulate system for potentiating the antiulcerogenic activity of the loaded APO has been described here. Methods: COS-nanoparticles (NPs) loaded with APO (using tripolyphosphate [TPP] as a cross-linker) were prepared by ionic gelation method and fully characterized. The chosen formula was extensively evaluated regarding in vitro release profile, kinetic analysis, and stability at refrigerated and room temperatures. Ultimately, the in vivo antiulcerogenic activity against ketoprofen (KP)-induced gastric ulceration in rats was assessed by macroscopic parameters including Paul's index and antiulcerogenic activity, histopathological examination, immunohistochemical (IHC) evaluation of cyclooxygenase-2 (COX-2) expression level in ulcerated gastric tissue, and biochemical measurement of oxidative stress markers and nitric oxide (NO) levels. Results: The selected NPs formula with COS (0.5 % w/v) and TPP (0.1% w/v) was the most appropriate one with drug entrapment efficiency percentage of 35.06%, particle size of 436.20 nm, zeta potential of +38.20 mV, and mucoadhesive strength of 51.22%. It exhibited a biphasic in vitro release pattern as well as high stability at refrigerated temperature for a 6-month storage period. APO-loaded COS-NPs provoked marvelous antiulcerogenic activity against KP-induced gastric ulceration in rats compared with free APO treated group, which was emphasized by histopathological, IHC, and biochemical studies. Conclusion: In conclusion, APO-loaded COS-NPs could be considered as a promising oral phytopharmaceutical nanoparticulate system for management of gastric ulceration.

Novel anti-inflammatory film as a delivery system for the external medication with bioactive phytochemical "Apocynin".

PURPOSE: Recently, Apocynin (APO) has emerged as a bioactive phytochemical with potent antioxidant and anti-inflammatory properties. No reports have been published so far concerning its topical application as a pharmaceutical dosage form for prospective use. To the best of our knowledge, this is the first study to fabricate novel anti-inflammatory film for external medication with APO. METHODS: APO film was prepared using casein (CAS) as a natural protein film former by solvent casting technique. The medicated film was extensively evaluated in terms of its various physicochemical characteristics, ex vivo skin permeation profile, stability, and finally in vivo anti-inflammatory activity on carrageenan-induced rat paw edema. RESULTS: The film represented satisfactory mechanical properties along with good flexibility. Fourier transform-infrared spectroscopy, differential scanning calorimetry, and X-ray diffractometry revealed possible solubility of APO in the amorphous CAS and inter- and intramolecular hydrogen bonding between the film components. The ex vivo skin permeation results of the medicated film demonstrated non-Fickian diffusion mechanism of the permeated drug. Application of APO film to rat paw before carrageenan-induced paw edema or after induction disclosed eminent anti-inflammatory activity expressed by marked decrease in paw swelling (%) and increase in edema inhibition rate (%). In addition, histopathologic examination revealed a significant decrease in inflammatory scores. The immunohistochemical expression levels of both nuclear factor kappa B and cyclooxygenase-2 were significantly suppressed. CONCLUSION: These results indicated that CAS film could be applied as a promising external delivery system for the anti-inflammatory APO.

Novel chitosan-based solid-lipid nanoparticles to enhance the bio-residence of the miraculous phytochemical "Apocynin".

Apocynin (APO), a specific NADPH oxidase inhibitor, is a bioactive phytochemical that exhibits versatile pharmacological activities. However, its rapid elimination and poor bioavailability represent great challenges to pharmaceutical scientists. Accordingly, novel chitosan-based APO-loaded solid lipid nanoparticles (CS,APO - loaded SLNS) were developed to address such obstacles. A full 24 factorial design of experiment approach was employed to evaluate the individual and combined effect of critical process parameters namely; the amount of glycerol tristearate (GTS, XA) and sucrose mono palmitate (SMP, XB) as well as the concentration of chitosan (CS, XC) and polyvinyl alcohol (PVA, XD), on different critical quality attributes. Full characterization and extensive in vitro-in vivo evaluations of the optimized SLNs formula were conducted. The optimized formula, with core (CS,APO) and shell (PVA), has enhanced oral and intravenous bioavailability in rats as clearly verified when compared with APO solution. Probably, PVA hindered opsonization intravenously and SLNs reduced pre-systemic effect. In conclusion, the novel chitosan-based SLNs system would open new vistas in potentiating the bioavailability and sustaining the effect of APO and other bioactive phytochemicals with comparable properties.

Polymeric micelles for potentiated antiulcer and anticancer activities of naringin.

Naringin is one of the most interesting phytopharmaceuticals that has been widely investigated for various biological actions. Yet, its low water solubility, limited permeability, and suboptimal bioavailability limited its use. Therefore, in this study, polymeric micelles of naringin based on pluronic F68 (PF68) were developed, fully characterized, and optimized. The optimized formula was investigated regarding in vitro release, storage stability, and in vitro cytotoxicity vs different cell lines. Also, cytoprotection against ethanol-induced ulcer in rats and antitumor activity against Ehrlich ascites carcinoma in mice were investigated. Nanoscopic and nearly spherical 1:50 micelles with the mean diameter of 74.80±6.56 nm and narrow size distribution were obtained. These micelles showed the highest entrapment efficiency (EE%; 96.14±2.29). The micelles exhibited prolonged release up to 48 vs 10 h for free naringin. The stability of micelles was confirmed by insignificant changes in drug entrapment, particle size, and retention (%) (91.99±3.24). At lower dose than free naringin, effective cytoprotection of 1:50 micelles against ethanol-induced ulcer in rat model has been indicated by significant reduction in mucosal damage, gastric level of malondialdehyde, gastric expression of tumor necrosis factor-alpha, caspase-3, nuclear factor kappa-light-chain-enhancer of activated B cells, and interleukin-6 with the elevation of gastric reduced glutathione and superoxide dismutase when compared with the positive control group. As well, these micelles provoked pronounced antitumor activity assessed by potentiated in vitro cytotoxicity particularly against colorectal carcinoma cells and tumor growth inhibition when compared with free naringin. In conclusion, 1:50 naringin-PF68 micelles can be represented as a potential stable nanodrug delivery system with prolonged release and enhanced antiulcer as well as antitumor activities.

Pivotal role of Acitretin nanovesicular gel for effective treatment of psoriasis: ex vivo-in vivo evaluation study.

The goal of the current study was to explore the potential benefits of Acitretin (Act) nanovesicular gel as a prospective antipsoriatic topical delivery system counteracting the drug challenges in terms of its extremely low aqueous solubility, instability, skin irritation, and serious systemic adverse effects. Act-loaded niosomes were successfully developed, entirely characterized, and optimized. Further evaluation of the optimized formula was conducted regarding its stability and ex vivo cytotoxicity on different cell lines. The optimized niosomal vesicles were then incorporated in gel base matrix and investigated by sequential ex vivo (skin permeation and deposition) and in vivo (skin irritation and antipsoriatic activity using mouse tail model) experiments. The optimized Act-loaded niosomes (span 60:cholesterol molar ratio 1:1) were spherical in shape and exhibited the highest entrapment efficiency (90.32±3.80%) with appropriate nanosize and zeta potential of 369.73±45.45 nm and -36.33±1.80 mV, respectively. Encapsulation of the drug in the nanovesicles was further emphasized by differential scanning calorimetric and powder X-ray diffraction studies. After 3 months storage at 4±1°C, the optimized formula preserved its stability. Act nano niosomal gel produced a remarkable enhanced ex vivo permeation profile up to 30 h and significant drug deposition in the viable epidermal-dermal layers compared with those of Act gel. The pronounced antipsoriatic activity of the medicated nano niosomes was proved ex vivo in HaCaT cells (a keratinocyte cell line). Topical application of Act nano niosomal gel to mouse tail model further established its distinct in vivo antipsoriatic superiority in terms of significantly higher orthokeratosis, drug activity, and reduction in epidermal thickness compared with the control and other gel formulations. Also, negligible skin irritation and better skin tolerability of Act nanovesicular gel were revealed by primary irritation index and histopathologic examination.

Potential Use of Polyvinyl Acetate-Polyvinylpyrrolidone Mixture for the Development of Atenolol Sustained Release Matrix Tablets: Optimization of Formulation through in Vitro-in Vivo Assessment Study.

The objective of this study was to develop sustained release matrix tablets of atenolol (AT) using different concentrations of polyvinyl acetate-polyvinylpyrrolidone mixture (KSR) (20, 30, or 40%) with various types of fillers such as spray dried lactose (SP.D.L), avicel pH 101 (AV), and emcompress (EMS). The physical characteristics of the prepared tablets were evaluated. Characterization of the optimized formulation was performed using Fourier transform (FT)-IR spectroscopy and differential scanning calorimetry (DSC). Moreover, the in vitro release profiles of AT formulations were investigated in different pH dissolution media. Drug release kinetics and mechanisms were also determined. The results revealed that there was no potential incompatibility of the drug with the polymer. The release profiles of AT were affected by the concentration of KSR, fillers used, and pH of the dissolution media. The drug release kinetic from most of the formulations obeyed Higuchi diffusion model. The selected formulae were investigated for their stability by storage at 30 and 40°C with atmospheric humidity and 75% relative humidity (RH), respectively. The results demonstrated that no change in the physicochemical properties of the tablets stored at 30°C/atmospheric RH in comparison with some changes at 40°C/75% RH. Finally, the in vivo study provided an evidence that the optimized AT tablet containing 40% KSR and SP.D.L exhibited prominent higher oral bioavailability and more efficient sustained-release effect than the drug alone or the commercial tablet product. It is noteworthy that KSR could be considered as a promising useful release retardant for the production of AT sustained release matrix tablets.

Self-Assembly PEGylation Retaining Activity (SPRA) Technology via a Host-Guest Interaction Surpassing Conventional PEGylation Methods of Proteins.

Polyethylene glycol (PEG) modification (PEGylation) is one of the best approaches to improve the stabilities and blood half-lives of protein drugs; however, PEGylation dramatically reduces the bioactivities of protein drugs. Here, we present "self-assembly PEGylation retaining activity" (SPRA) technology via a host-guest interaction between PEGylated ß-cyclodextrin (PEG-ß-CyD) and adamantane-appended (Ad) proteins. PEG-ß-CyD formed stable complexes with Ad-insulin and Ad-lysozyme to yield SPRA-insulin and SPRA-lysozyme, respectively. Both SPRA-proteins showed high stability against heat and trypsin digest, comparable with that of covalently PEGylated protein equivalents. Importantly, the SPRA-lysozyme possessed ca. 100% lytic activity, whereas the activity of the covalently PEGylated lysozyme was ca. 23%. Additionally, SPRA-insulin provided a prolonged and peakless blood glucose profile when compared with insulin glargine. It also showed no loss of activity. In contrast, the covalently PEGylated insulin showed a negligible hypoglycemic effect. These findings indicate that SPRA technology has potential as a generic method, surpassing conventional PEGylation methods for proteins.

Enhanced in vitro cytotoxicity and anti-tumor activity of vorinostat-loaded pluronic micelles with prolonged release and reduced hepatic and renal toxicities.

Vorinostat is the first histone deacetylase inhibitor approved by US FDA for use in cancer therapy. However, its limited aqueous solubility, low permeability, and suboptimal pharmacokinetics hinder its delivery. Thus, in this study, micelles of vorinostat with each of pluronic F68 (PF68) and pluronic F127 (PF127) were developed and optimized based on drug loading and entrapment. The optimized micelles were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), zeta analyzer, and electron transmission microscopy. Their in vitro release, stability, in vitro cytotoxicity against HepG2, Caco-2, and MCF-7 cell lines, and finally, in vivo antitumor activity in mice bearing Ehrlich Ascites Carcinoma (EAC) were assessed. The highest entrapment efficiency was 99.09±2.16% and 94.19±2.37% for micelles of 1:50 drug to polymer ratio with each of PF127 and PF68, respectively. These micelles were nearly spherical with nanoscopic mean diameters of 72.61±10.66nm for PF68 and 91.88±10.70nm for PF127 with narrow size distribution. The micelles provided prolonged release at phosphate buffer saline pH7.4 up to 24h for PF68 and 72h for PF127. Potentiation of in vitro cytotoxicity of vorinostat was more pronounced with PF127 micelles particularly against MCF-7 cells. Compared with free vorinostat, the micelles with PF127 were more effective in inhibiting tumor growth as well as exhibiting significantly (p<0.05) diminished hepatic and renal toxicities. In conclusion, 1:50 vorinostat-PF127 micelles may facilitate i.v. formulations and can be suggested as a promising stable and safe nanoparticulate delivery system with prolonged release and potentiated cytotoxicity.

Investigation and Evaluation of an in Situ Interpolymer Complex of Carbopol with Polyvinylpyrrolidone as a Matrix for Gastroretentive Tablets of Ranitidine Hydrochloride.

Carbopol (CP) is a biocompatible bioadhesive polymer used as a matrix for gastroretentive (GR) tablets, however, its rapid hydration shortens its bioadhesion and floating when incorporated in effervescent formulae. The interpolymer complexation of CP with polyvinylpyrrolidone (PVP) significantly reduced the excessive hydration of CP, prolonging floating and maintaining the mucoadhesiveness. In early attempts, a lengthy process was followed to prepare such an interpolymer complex. In this study, an in situ interpolymer complexation between CP and two grades of PVP (K25 and K90) in 0.1 N HCl was investigated and characterized by Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Hence, directly compressed GR tablets of different combinations of PVP and CP with sodium bicarbonate (SB) as an effervescent agent were examined for prolonged gastroretention and sustained release of ranitidine hydrochloride (RHCl) as a model drug. Tablets were evaluated for in vitro buoyancy, bioadhesiveness, swelling, and drug release in 0.1 N HCl. All GR tablets containing PVP-CP combinations achieved more prolonged floating (>24 h) than CP tablets (5.2 h). Their bioadhesiveness, swelling, and drug release were dependent on the PVP molecular weight and its ratio to CP. Drug release profiles of all formulae followed non-Fickian diffusion. Formula containing the PVP K90-CP combination at a respective ratio of 1 : 3 (P90C13) was a promising system, exhibiting good floating and bioadhesive properties as well as sustained drug release. Abdominal X-ray imaging of P90C13 formula, loaded with barium sulfate, in six healthy volunteers showed a mean gastric retention period of 6.8±0.3 h.

Gastroretentive Matrix Tablets of Boswellia Oleogum Resin: Preparation, Optimization, In Vitro Evaluation, and Cytoprotective Effect on Indomethacin-Induced Gastric Ulcer in Rabbits.

Currently available anti-ulcer drugs suffer from serious side effects which limited their uses and prompted the need to search for a safe and efficient new anti-ulcer agent. Boswellia gum resin (BR) emerged as a safe, efficient, natural, and economic potential cytoprotective agent. Thus, it is of medical importance to develop gastroretentive (GR) formulations of BR to enhance its bioavailability and anti-ulcer efficacy. Early attempts involved the use of organic solvents and non-applicability to large-scale production. In this study, different tablet formulations were prepared by simple direct compression combining floating and bioadhesion mechanisms employing hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), pectin (PC), and/or carbopol (CP) as bioadhesive polymers and sodium bicarbonate (SB) as a gas former. The prepared tablets were subjected for assessment of swelling, floating, bioadhesion, and drug release in 0.1 N HCl. The optimized GR formulation was examined for its protective effect on the gastric ulcer induced by indomethacin in albino rabbits compared with lactose tablets. The obtained results disclosed that swelling, floating, bioadhesion, and drug release of the GR tablets of BR depend mainly on the nature of the matrix and the ratio of polymer combinations. Moreover, a combination of SCMC-CP in a ratio of 2:1 (SCP21) exhibited desirable floating, bioadhesion, swelling, and extended drug release. Also, a 6-h pretreatment with SCP21 tablets decreased the severity of inflammation and number of bleeding spots among ulcer-induced rabbits in comparison to those treated with lactose tablets.

Potential Use of Thioalkylated Mannose-Modified Dendrimer (G3)/α-Cyclodextrin Conjugate as an NF-κB siRNA Carrier for the Treatment of Fulminant Hepatitis.

NF-κB and its associated pathways are complicatedly concerned about hepatic homeostasis. Discriminating inhibition of NF-κB signaling has been expected to treat various liver diseases including fulminant hepatitis. To clarify the potential use of thioalkylated mannose-appended dendrimer (generation 3; G3) conjugates with α-cyclodextrin with average degree of substitution of mannose (DSM4) (Man-S-α-CDE (G3, DSM4)) as a novel antigen presenting cell (APC)-specific siRNA carrier, we evaluated the RNAi effect of NF-κB p65 siRNA (sip65) complex with Man-S-α-CDE (G3, DSM4) both in vitro and in vivo. Man-S-α-CDE (G3, DSM4)/sip65 complex significantly suppressed NF-κB p65 mRNA expression and nitric oxide (NO) production from lipopolysaccharide (LPS)-stimulated NR8383 cells, a rat alveolar macrophage cell line, by adequate physicochemical properties and mannose receptor-mediated cellular uptake. Intravenous injection of Man-S-α-CDE (G3, DSM4)/sip65 complex extended the survival rate of LPS-induced fulminant hepatitis model mice. In addition, intravenous administration of Man-S-α-CDE (G3, DSM4)/sip65 complex had the potential to induce the in vivo RNAi effect by significant suppression of mRNA expression of NF-κB p65 and inflammatory cytokines in the liver of fulminant hepatitis model mice induced by LPS/d-galactosamine (d-Gal) without any significant side effects. Also, the serum levels of enzymes were significantly attenuated by injection of Man-S-α-CDE (G3, DSM4)/sip65 complex in fulminant hepatitis model mice. Collectively, these results suggest that Man-S-α-CDE (G3, DSM4) has the potential as a novel APC-selective sip65 carrier for the treatment of LPS/d-Gal-induced fulminant hepatitis in mice.

Design and Evaluation of the Highly Concentrated Human IgG Formulation Using Cyclodextrin Polypseudorotaxane Hydrogels.

To achieve the potent therapeutic effects of human immunoglobulin G (IgG), highly concentrated formulations are required. However, the stabilization for highly concentrated human IgG is laborious work. In the present study, to investigate the potentials of polypseudorotaxane (PPRX) hydrogels consisting of polyethylene glycol (PEG) and α- or γ-cyclodextrin (α- or γ-CyD) as pharmaceutical materials for highly concentrated human IgG, we designed the PPRX hydrogels including human IgG and evaluated their pharmaceutical properties. The α- and γ-CyDs formed PPRX hydrogels with PEG (M.W. 20,000) even in the presence of highly concentrated human IgG (>100 mg/mL). According to the results of (1)H-NMR, powder X-ray diffraction, and Raman microscopy, the formation of human IgG/CyD PPRX hydrogels was based on physical cross-linking arising from their columnar structures. The release profiles of human IgG from the hydrogels were in accordance with the non-Fickian diffusion model. Importantly, the stabilities of human IgG included into the hydrogels against thermal and shaking stresses were markedly improved. These findings suggest that PEG/CyD PPRX hydrogels are useful to prepare the formulation for highly concentrated human IgG.

Potential use of niosomal hydrogel as an ocular delivery system for atenolol.

Niosomes have been reported as possible approach to improve the low corneal penetration and bioavailability characteristics for many drugs. The purpose of this study was to prepare and characterize an effective ocular niosomal hydrogel containing 0.5% (w/v) atenolol which is ß1 adrenoceptor blocker for treatment of glaucoma. Thin film hydration method was used for the preparation of niosomes using Span 60 and cholesterol at different molar ratios. Niosomes were characterized using laser diffraction particle size analyzer, transmission electron microscopy, and differential scanning calorimetry. The results showed that higher entrapment efficiency (80.7%±1.2) was obtained from niosomes prepared using Span 60/cholesterol at a 2 : 1 molar ratio. Stability study revealed that a fairly high retention of atenolol inside vesicles (83.1%±2.35) up to a period of 3 months at 4°C. It was found that niosomal hydrogel formulation using carbopol 934P significantly exhibited sustained in vitro release of the drug compared with free drug solution and other polymeric hydrogels. The intraocular pressure (IOP) lowering activity of selected atenolol formulations was determined and compared with that of atenolol solution. It is worth noting that niosomal hydrogel formulation was found to show the most significant prolonged decrease in IOP, suggesting that niosomal hydrogel could be a promising delivery system for atenolol.

Some variables affecting the characteristics of Eudragit E-sodium alginate polyelectrolyte complex as a tablet matrix for diltiazem hydrochloride.

Eudragit E (EE)-sodium alginate (SA) polyelectrolyte complexes (PECs) were prepared at pH 4 and 5.8 using sodium alginate of high (SAH) and low viscosity (SAL). The optimum EE-SA complexation mass ratio was determined using viscosity measurements. Interactions between EE and SA in PECs were characterized by Fourier transform infra-red spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Diltiazem hydrochloride (DTZ HCl) tablets were prepared using the prepared EE-SA PECs and their physical mixtures at different ratios as matrices. Tablets were evaluated for swelling characteristics and in vitro drug release. Tablets containing EE-SAH physical mixtures of ratios (1.5:1 and 1:3) as matrices were effective in achieving sustained release of DTZ HCl, where the percent drug released was significantly (p < 0.05) decreased compared to that from tablets either containing the same ratios of EE-SAL physical mixtures or the preformed EE- -SAH and EE-SAL PECs.

Potential use of gamma-cyclodextrin polypseudorotaxane hydrogels as an injectable sustained release system for insulin.

The development of injectable hydrogels for protein delivery is a major challenge. In this study, insulin/alpha-cyclodextrin (alpha-CyD) and gamma-CyD polypseudorotaxane (PPRX) hydrogels were prepared through inclusion complexation between high molecular weight poly(ethylene glycol) (PEG) and CyDs. The alpha-CyD and gamma-CyD PPRX hydrogels were formed by inserting one PEG chain in the alpha-CyD cavity and two PEG chains in the gamma-CyD cavity. Insulin/CyD PPRX hydrogel formation was based on physical crosslinking induced by self-assembling without chemical crosslinking reagent. The supramolecular structures of insulin/CyD PPRX hydrogels were confirmed with (1)H nuclear magnetic resonance ((1)H NMR), X-ray diffraction, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release study showed that the release rate of insulin from the CyDs PPRX hydrogels decreased in the order of gamma-CyD PPRX hydrogel>alpha-CyD PPRX hydrogel. This decrease was controlled by the addition of CyDs to the medium. The serum insulin level after subcutaneous administration of gamma-CyD PPRX hydrogel to rats was significantly prolonged, accompanying with an increase in the area under serum concentration-time curve, which was clearly reflected in the prolonged hypoglycemic effect. In conclusion, these results suggest the potential use of gamma-CyD PPRX hydrogel as an injectable sustained release system for insulin.

Comparison of different perrmeation enhancers on topical ketoconazole formulations.

The clinical efficacy of five ketoconazole (CAS 65277-42-1) topical formulations (three gels and two creams) was evaluated in 50 patients suffering from fungal infections in an open uncontrolled pilot study. Each formulation contained selected permeation enhancers providing high permeability in vitro. The patients were randomly divided into five groups each of ten persons. Each group was assigned to a selected topical formula which was applied to the diseased skin twice daily for four weeks or until complete clinical improvement. The clinical evaluation of treatment effects was based on the following criteria: size of lesion, erythema, scaling and severity of itching (four grades each). The patients were considered cured after the disappearance of these clinical symptoms and negative potassium hydroxide and Wood's light examination tests during the follow-up period. The results showed that the overall therapeutic response to the treatment was 96.7% and 93% for the hydroxypropylmethyl cellulose gel containing menthol and sodium carboxymethyl cellulose gel containing isopropyl myristate, respectively. Creams (w/o and o/w) achieved 90% and 87% improvement after 2.5 weeks, respectively. The lowest clinical response (86.5% improvement) with the longest duration of treatment (3 weeks) was observed with sodium carboxymethyl cellulose gel containing oleic acid.