Electrospun vancomycin-loaded nanofibers for management of methicillin-resistant Staphylococcus aureus-induced skin infections.

Skin damage exposes the underlying layers to bacterial invasion, leading to skin and soft tissue infections. Several pathogens have developed resistance against conventional topical antimicrobial treatments and rendered them less effective. Recently, several nanomedical strategies have emerged as a potential approach to improve therapeutic outcomes of treating bacterial skin infections. In the current study, nanofibers were utilized for topical delivery of the antimicrobial drug vancomycin and evaluated as a promising tool for treatment of topical skin infections. Vancomycin-loaded nanofibers were prepared via electrospinning technique, and vancomycin-loaded nanofibers of the optimal composition exhibited nanosized uniform smooth fibers (ca. 200 nm diameter), high drug entrapment efficiency and sustained drug release patterns over 48 h. In vitro cytotoxicity assays, using several cell lines, revealed the biocompatibility of the drug-loaded nanofibers. In vitro antibacterial studies showed sustained antibacterial activity of the vancomycin-loaded nanofibers against methicillin-resistant Staphylococcus aureus (MRSA), in comparison to the free drug. The nanofibers were then tested in animal model of superficial MRSA skin infection and demonstrated a superior antibacterial efficiency, as compared to animals treated with the free vancomycin solution. Hence, nanofibers might provide an efficient nanodevice to overcome MRSA-induced skin infections and a promising topical delivery vehicle for antimicrobial drugs.

Enhancing Docetaxel Delivery to Multidrug-Resistant Cancer Cells with Albumin-Coated Nanocrystals.

Intravenous delivery of poorly water-soluble anticancer drugs such as docetaxel (DTX) is challenging due to the low bioavailability and the toxicity related to solubilizing excipients. Colloidal nanoparticles are used as alternative carriers, but low drug loading capacity and circulation instability limit their clinical translation. To address these challenges, DTX nanocrystals (NCs) were prepared using Pluronic F127 as an intermediate stabilizer and albumin as a functional surface modifier, which were previously found to be effective in producing small and stable NCs. We hypothesize that the albumin-coated DTX NCs (DTX-F-alb) will remain stable in serum-containing medium so as to effectively leverage the enhanced permeability and retention effect. In addition, the surface-bound albumin, in its native form, may contribute to cellular transport of NCs through interactions with albumin-binding proteins such as secreted protein acidic and rich in cysteine (SPARC). DTX-F-alb NCs showed sheet-like structure with an average length, width, and thickness of 284 ± 96, 173 ± 56, and 40 ± 8 nm and remained stable in 50% serum solution at a concentration greater than 10 µg/mL. Cytotoxicity and cellular uptake of DTX-F-alb and unformulated (free) DTX were compared on three cell lines with different levels of SPARC expression and DTX sensitivity. While the uptake of free DTX was highly dependent on DTX sensitivity, DTX-F-alb treatment resulted in relatively consistent cellular levels of DTX. Free DTX was more efficient in entering drug-sensitive B16F10 and SKOV-3 cells than DTX-F-alb, with consistent cytotoxic effects. In contrast, multidrug-resistant NCI/ADR-RES cells took up DTX-F-alb more than free DTX with time and responded better to the former. This difference was reduced by SPARC knockdown. The high SPARC expression level of NCI/ADR-RES cells, the known affinity of albumin for SPARC, and the opposing effect of SPARC knockdown support that DTX-F-alb have exploited the surface-bound albumin-SPARC interaction in entering NCI/ADR-RES cells. Albumin-coated NC system is a promising formulation for the delivery of hydrophobic anticancer drugs to multidrug-resistant tumors.

Nanostructured lipid carriers for improved oral delivery and prolonged antihyperlipidemic effect of simvastatin.

The purpose of the current study is to develop nanostructured lipid carriers (NLCs) for the delivery of the antihyperlipidemic drug simvastatin (SIM) to increase its extremely low oral bioavailability (<5%) and prolong its antihyperlipidemic effect. NLCs were prepared via emulsification-solvent evaporation technique followed by ultrasonication, and the effect of composition of the nanocarriers on the particle size, size distribution, surface charge, entrapment efficiency, drug release kinetics and physical stability was extensively studied. NLCs exhibited nanosized (<200nm) spherical morphologies with narrow size distribution and high drug entrapment efficiency (>75%), sustained drug release pattern, and negative surface charge (zeta potential of -35-40mV) that imparts sufficient electrostatic physical stability. When tested in vivo, SIM-NLCs of the optimal composition demonstrated improved and prolonged reduction in the total cholesterol and non-high density lipoprotein cholesterol levels, as compared to the drug suspension. After oral administration of a single dose of SIM-NLC, 4-fold increase in bioavailability was observed, as compared to the SIM suspension. Hence, NLCs might provide efficient nanodevices for the management of hyperlipidemia and promising drug delivery systems to enhance SIM oral bioavailability.

Thermosensitive bioadhesive gels for the vaginal delivery of sildenafil citrate: in vitro characterization and clinical evaluation in women using clomiphene citrate for induction of ovulation.

OBJECTIVE: The objective of this study is to develop and characterize in situ thermosensitive gels for the vaginal administration of sildenafil as a potential treatment of endometrial thinning occurring as a result of using clomiphene citrate for ovulation induction in women with type II eugonadotrophic anovulation. While sildenafil has shown promising results in the treatment of infertility in women, the lack of vaginal pharmaceutical preparation and the side effects associated with oral sildenafil limit its clinical effectiveness. METHODS: Sildenafil citrate in situ forming gels were prepared using different grades of Pluronic® (PF-68 and PF-127). Mucoadhesive polymers as sodium alginate and hydroxyethyl cellulose were added to the gels in different concentrations and the effect on gel properties was studied. The formulations were evaluated in terms of viscosity, gelation temperature (Tsol-gel), mucoadhesion properties, and in vitro drug release characteristics. Selected formulations were evaluated in women with clomiphene citrate failure due to thin endometrium (Clinicaltrial.gov identifier NCT02766725). RESULTS: The Tsol-gel decreased with increasing PF-127 concentration and it was modulated by addition of PF-68 to be within the acceptable range of 28-37 °C. Increasing Pluronic® concentration increased gel viscosity and mucoadhesive force but decreased drug release rate. Clinical results showed that the in situ sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow with no reported side effects. Further, these results were achieved at lower frequency and duration of drug administration. CONCLUSION: Sildenafil thermosensitive vaginal gels might result in improved potential of pregnancy in anovulatory patients with clomiphene citrate failure due to thin endometrium.

From The Mine to Cancer Therapy: Natural and Biodegradable Theranostic Silicon Nanocarriers from Diatoms for Sustained Delivery of Chemotherapeutics.

Drug delivery using synthetic nanoparticles including porous silicon has been extensively used to overcome the limitations of chemotherapy. However, their synthesis has many challenges such as lack of scalability, high cost, and the use of toxic materials with concerning environmental impact. Nanoscale materials obtained from natural resources are an attractive option to address some of these disadvantages. In this paper, a new mesoporous biodegradable silicon nanoparticle (SiNP) drug carrier obtained from natural diatom silica mineral available from the mining industry is presented. Diatom silica structures are mechanically fragmented and converted into SiNPs by simple and scalable magnesiothermic reduction process. Results show that SiNPs have many desirable properties including high surface area, high drug loading capacity, strong luminescence, biodegradability, and no cytotoxicity. The in-vitro release results from SiNPs loaded with anticancer drugs (doxorubicin) demonstrate a pH-dependent and sustained drug release with enhanced cytotoxicity against cancer cells. The cells study using doxorubicin loaded SiNPs shows a significantly enhanced cytotoxicity against cancer cells compared with free drug, suggesting their considerable potential as theranostic nanocarriers for chemotherapy. Their low-cost manufacturing using abundant natural materials and outstanding chemotherapeutic performance has made them as a promising alternative to synthetic nanoparticles for drug delivery applications.

Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate.

The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug's bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to surfactant ratios. The niosomes were characterized for size, zeta-potential, and entrapment efficiency. The selected niosomal formulation was incorporated into polymeric films using hydroxypropyl methyl cellulose E15 and methyl cellulose as film-forming polymers and Avicel as superdisintegrant. The physical characteristics (appearance, texture, pH, uniformity of weight and thickness, disintegration time, and palatability) of the prepared films were studied, in addition to evaluating the in vitro drug release, stability, and in vivo pharmacokinetics in rabbits. The release of the drug from the medicated film was fast (99.9% of the drug was released within 30 minutes), while the drug loaded into the niosomes, either incorporated into the film or not, showed only 22.85% drug release within the same time. The selected sublingual film showed significantly higher rate of drug absorption and higher drug plasma levels compared with that of commercial oral tablet. The plasma levels remained detectable for 24 hours following sublingual administration, compared with only 12 hours after administration of the oral tablet. In addition, the absolute bioavailability of the drug (ie, relative to intravenous administration) following sublingual administration was found to be significantly higher (91.06%±13.28%), as compared with that after oral tablet administration (39.37%±11.4%). These results indicate that the fast dissolving niosomal film could be a promising delivery system to enhance the bioavailability and prolong the therapeutic effect of metoprolol tartrate.

Development and evaluation of viscosity-enhanced nanocarrier (VEN) for oral insulin delivery.

Solid lipid nanoparticles (SLN) have demonstrated good potential for oral peptide delivery. However, their hydrophobic nature generally accounts for low peptide entrapment efficiency (EE%). In this study, a new strategy was adopted to improve peptide EE% by incorporating a hydrophilic viscosity-enhancing agent (VA) within SLN cores to develop viscosity enhanced nanocarriers (VEN). Three agents namely, propylene glycol (PG), polyethylene glycol (PEG) 400 and PEG 600, were tested with human insulin serving as a model peptide drug. The effects of VA were both concentration- and type-dependent. 70% w/w PG had achieved the highest EE% (54.5%), versus the two PEGs, compared to only 20.4% in unmodified SLN. PG based VEN had demonstrated good dispersion stability at gastrointestinal (GI) pHs and preferential uptake by intestinal Caco2 cells while showing low cytotoxicity. Additionally, they preserved the integrity of insulin and significantly protected it against GI enzymatic degradation. Freeze dried VEN had shown good stability upon storage at -20°C. Orally administered insulin-VEN had achieved good hypoglycemic effect in fasted rats with relative bioavailability of 5.1%. To conclude, an easily implementable technique to improve peptide entrapment within SLN has been validated, and the resulting VEN had proved promising efficacy for oral peptide delivery.

Methocel-Lipid Hybrid Nanocarrier for Efficient Oral Insulin Delivery.

Even with the use of double-emulsion technique for preparation, the hydrophobic nature of solid lipid nanoparticles (SLNs) limits their encapsulation efficiency (EE%) for peptides such as insulin. In this study, we hypothesize that inclusion of Methocel into SLN to form Methocel-lipid hybrid nanocarriers (MLNs) will significantly enhance insulin EE% without compromising the various characteristics of SLN favorable for oral drug delivery. Our data show that incorporation of 2% wt/wt of Methocel A15C had doubled insulin EE% (around 40%) versus conventional SLN prepared using standard double emulsion technique. MLN significantly protected the entrapped insulin against chymotrypsin degradation at gastrointestinal pH. Using intestinal epithelial cells Caco2 as a model, it was shown that MLN could be extensively taken up by Caco2 cells while demonstrating low cytotoxicity. The results indicate that MLN have preserved the key advantages of SLN (biocompatibility, low cytotoxicity, good drug protection, and good interaction with cells) while overcoming their key limitation for efficient peptide entrapment. Based on this, MLN may serve as a promising nanocarrier for oral delivery of peptides.

Transdermal delivery of meloxicam using niosomal hydrogels: in vitro and pharmacodynamic evaluation.

Non-ionic surfactant vesicles were prepared using Span-60 and cholesterol in the mass ratios of 1:1, 2:1, 1:2 and 3:1 for transdermal delivery of an anti-inflammatory drug meloxicam (MXM). The drug encapsulation efficiencies and particle size were observed in the range of 32.9-80.7% and 56.5-133.4 nm, respectively. Three different gel bases were also prepared using Poloxamer-407, Chitosan and Carbopol-934 as polymers to study the performance of the in vitro release of the drug. Prepared gels were also converted into niosomal gels. In vitro release characteristics of MXM from different gels were carried out using dialysis membrane in phosphate buffer (pH 7.4). The poloxamer-407 gel or niosomal poloxamer-407 gel showed the superior drug release over the other formulations. The release data were treated with various mathematical models to assess the relevant parameters. The results showed that the release of MXM from the prepared gels and niosomal gels followed Higuchi's diffusion model. The flux of MXM was found to be independent on the viscosity of the formulations. The anti-inflammatory effects of MXM from different niosomal gel formulations were evaluated using carrageenan-induced rat paw edema method, which showed superiority of niosomal gels over conventional gels.

Liposomal gels for site-specific, sustained delivery of celecoxib: in vitro and in vivo evaluation.

The objective of this work was to evaluate liposome-containing gel formulations for the sustained, site-specific delivery of celecoxib (CXB). Liposomes composed of phosphadtidylcholine (and various amounts of cholesterol (Ch) were prepared using thin film hydration and characterized for encapsulation efficiency, vesicle size, and drug-excipient interaction using differential scanning calorimetry and Fourier-transform infrared spectroscopy. The selected liposome formulation was incorporated in different gel formulations: the Ch ratio affected the encapsulation efficiency of the drug, by increasing Ch ratio up until 1:1 the encapsulation efficiency increased. Further increasing the Ch ratio resulted in decreasing encapsulation efficiency. In vitro drug release and skin permeation studies showed sustained release and enhanced permeation compared with gel formulations containing free drug. In the rat paw edema test, the anti-inflammatory activity of the selected liposomal gel formulation was higher and more sustained compared with that of the nonliposomal gel formulation containing free drug. These results suggest that the liposome-containing gels are promising formulations for sustained, site-specific delivery of CXB.

Solubility and dissolution enhancement of tadalafil using self-nanoemulsifying drug delivery system.

The aim of this study was to develop and evaluate self-nanoemulsifying drug delivery system (SNEDDS) of tadalafil (TDL) in order to enhance its aqueous solubility and dissolution rate. TDL SNEDDS were developed by aqueous phase titration method via construction of pseudo-ternary phase diagrams. The formulations which passed thermodynamic stability and self-nanoemulsification tests were further characterized in terms of droplet size, viscosity, % transmittance and drug content. Selected SNEDDS and drug suspension were subjected to in vitro drug release studies via dialysis membrane in phosphate buffer (pH 6.8). In vitro drug release studies showed 96.6% release of TDL from optimized SNEDDS F5 as compared to only 12.4% from drug suspension after 24 h of study. The results of solubility studies showed 1434 folds enhancement in TDL solubility from optimized SNEDDS F5 as compared to its aqueous solubility. Overall, these results indicated that developed SNEDDS could be successfully used to enhance solubility and dissolution rate of poorly soluble drugs such as TDL.

Comparative topical delivery of antifungal drug croconazole using liposome and micro-emulsion-based gel formulations.

The aim of this study was to develop liposomal-based (LBGF) and micro-emulsion-based (MBGF) gel formulations of croconazole to compare their topical delivery potential. Conventional gels were also prepared using various polymers such as sodium carboxymethyl cellulose (SCMC), Poloxamer 407, Carbopol 971P and chitosan. The in vitro release of croconazole from conventional gel formulations, LBGF and MBGF were carried out using cellophane membrane as permeation membrane. However, in vitro skin permeations studies of all formulations were carried out using rat skin. The results of the drug release/skin permeation studies indicated that the highest release was obtained from SCMC followed by chitosan, Poloxamer 407 and finally Carbopol 971P gel. Therefore, liposomes and micro-emulsions were loaded on Carbopol 971P gel. The drug release and skin permeation of croconazole from different LBGF and MBGF showed that MBGF had superior release/permeation than LBGF. MBGF having ethanol as co-surfactant showed higher release/permeation of drug than MBGF-containing propylene glycol. The analysis of data according to different kinetic models indicated that the release of drug from different LBGF and MBGF followed the Higuchi model. The antimicrobial activity of the different LBGF and MBGF of croconazole was carried out by measuring the inhibition zone (mm) and compared by the effect of miconazole cream as control. The different LBGF and MBGF showed an excellent activity against different species of fungi as compared with miconazole cream. Overall, these results indicated that developed LBGF and MBGF could have great potential for topical delivery of croconazole.

Development and characterization of thermosensitive pluronic-based metronidazole in situ gelling formulations for vaginal application.

The purpose of this study was to develop pluronic-based in situ gelling formulations of metronidazole (MTZ) for treatment of bacterial vaginosis, aimed at prolonging the residence time, controlling drug release, enhancing efficacy, decreasing recurrence, and increasing patient compliance. The in situ gel formulations were prepared using different concentrations of pluronic F-127 (PF-127) alone and in combination with pluronic F-68 (PF-68). The prepared formulations were evaluated for their gelation temperature (T(gel)), in vitro drug release, rheological properties, mucoadhesion properties and tolerability by vaginal mucosa in tissue levels. The T(gel) decreased with increasing PF-127 concentration. The T(gel) was modulated by addition of PF-68 to be within the acceptable range of 25-37 °C. With increasing pluronic concentration, the in vitro drug release decreased, viscosity and mucoadhesive force increased. Histopathological examination of rabbit vaginas from the control and treated groups revealed normal histology of the vagina and cervix. Based on the in vitro evaluation of prepared formulations, the in situ gelling liquid formulated with PF-127/PF-68 (20/10 %, m/m) was selected for further clinical evaluation.

Doxycycline in the treatment of bleeding with DMPA: a double-blinded randomized controlled trial.

BACKGROUND: Increased matrix metalloproteinase (MMP) activity in the endometrium is a predisposing factor for bleeding with depot medroxy progesterone acetate (DMPA) injectable contraception. Doxycycline (DOX) has been proven in vitro to inhibit MMP-mediated degradation of stromal matrix. The current study examined the effect of DOX compared to placebo in treating a current bleeding episode during DMPA use. STUDY DESIGN: A double-blinded randomized controlled trial was conducted in Assiut, Egypt. DMPA users with current bleeding episode were counseled to participate. Women who agreed to participate were randomly assigned to receive 100 mg DOX twice daily for 5 days (34 patients) or an identical placebo (34 patients). All participants were asked to report bleeding and spotting days in a menstrual diary. All participants were followed for 3 months after treatment. This trial was registered (NCT01254799). RESULTS: The relative risk to stop a bleeding episode within 10 days of starting treatment was 0.88 (confidence interval 0.64-1.21) in the treatment group compared to the control. DOX treatment caused no significant difference compared to placebo in the number of bleeding and/or spotting days in the 3 months following the treatment. CONCLUSION: Doxycycline as MMP inhibitor is not effective in stopping a current attack of bleeding with DMPA. It also does not improve the bleeding characteristics of women for the subsequent 3 months following the treatment.

Pilot randomized trial for treatment of bacterial vaginosis using in situ forming metronidazole vaginal gel.

AIM: To compare the efficacy of a novel vaginal delivery system for metronidazole (0.8% MTZ in situ gel) versus a conventional MTZ vaginal gel product in the treatment of bacterial vaginosis (BV). MATERIAL AND METHODS: All consecutive patients who presented to a tertiary care hospital with symptoms suggestive of BV were approached to participate in the study. Forty-two eligible participants were randomly assigned to either MTZ in situ gel or a conventional vaginal gel product twice daily for 5 days. All participants were re-examined after one and 4 weeks of the beginning of treatment to ensure cure of infection and any side-effects. RESULTS: Demographic criteria of the participants were comparable in the two treatment groups. The cure rate after one week from the treatment was 85% in the in situ gel group and 71.4% in the conventional vaginal gel group (P = 0.294), while after 4 weeks, the cure rate showed significant difference in the in situ gel group as compared to the conventional vaginal gel group (16/20 [80%]) and (9/19 [47.4%]), respectively (P = 0.034). CONCLUSION: Pilot testing showed that in situ MTZ vaginal gel is more effective than the conventional vaginal gel for long-term cure of BV. These findings suggest a novel and efficient long-term treatment of BV.

Improvement of solubility and dissolution rate of indomethacin by solid dispersions in Gelucire 50/13 and PEG4000.

The aim of this study was to prepare and characterize solid dispersions of water insoluble non-steroidal anti-inflammatory drug, indomethacin (IND), with polyethylene glycol 4000 (PEG4000) and Gelucire 50/13 (Gelu.) for enhancing the dissolution rate of the drug. The solid dispersions (SDs) were prepared by hot melting method at 1:1, 1:2 and 1:4 drug to polymer ratios. Scanning electron microscopy (SEM), X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to examine the physical state of the drug. Furthermore, the solubility and the dissolution rate of the drug in its different systems were explored. The data from the XRD showed that the drug was still detectable in its solid state in all SDs of IND-Gelu. and disappeared in case of higher ratio of IND-PEG4000. DSC thermograms showed the significant change in melting peak of the IND when prepared as SDs suggesting the change in crystallinity of IND. The highest ratio of the polymer (1:4) enhanced the drug solubility about 4-folds or 3.5-folds in case of SDs of IND-PEG or IND-Gelu., respectively. An increased dissolution rate of IND at pH 1.2 and 7.4 was observed when the drug was dispersed in these carriers in form of physical mixtures (PMs) or SDs. IND released faster from the SDs than from the pure crystalline drug or the PMs. The dissolution rate of IND from its PMs or SDs increased with an increasing amount of polymer.

Excellent absorption enhancing characteristics of NO donors for improving the intestinal absorption of poorly absorbable compound compared with conventional absorption enhancers.

The characteristics of NO donors, NOC5 [3-(2-hydroxy-1-(1-methylethyl-2-nitrosohydrazino)-1-propanamine), NOC12 [N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine] and SNAP [S-nitroso-N-acetyl-DL-penicillamine] as absorption enhancers for poorly absorbable drugs were examined in rats using an in situ closed loop method. They were compared with a group of conventional absorption enhancers including sodium glycocholate (NaGC), sodium caprate (NaCap), sodium salicylate (NaSal) and n-dodecyl-beta-D-maltopyranoside (LM). 5(6)-carboxyfluorescein (CF) was used as a model drug to investigate effectiveness, site-dependency, and concentration-dependency of the tested enhancers. Overall, the NO donors can improve the intestinal absorption of CF at low concentration (5 mM), whereas higher concentration was required for the conventional absorption enhancers to elicit the absorption enhancing effect. In the small intestine, SNAP was the most effective absorption enhancers, although its concentration (5 mM) was lower than the conventional absorption enhancers (20 mM). On the other hand, LM and NaCap as well as the three NO donors were effective to improve the colonic absorption of CF. In the regional difference in the absorption enhancing effects, the NO donors showed significant effects in all intestinal regions, whereas we observed a regional difference in the absorption enhancing effect of the other conventional absorption enhancers. In the conventional enhancers, the absorption enhancing effects were generally greater in the large intestine than those in the small intestine. LM and NaCap were ineffective in the jejunum, although they were effective for improving the absorption of CF in the colon. NaSal was ineffective in both the jejunum and the colon. The absorption enhancement produced by NO donors was greatly affected by increasing the enhancer concentration from 3 to 5 mM, but only a slight increase was obtained when the concentration was raised to 10 mM. Similar results were obtained for the other enhancers over the range of 10 to 20 mM, but the absorption enhancing effects of these enhancers were almost saturated above these concentrations. These results suggest that NO donors possess excellent effectiveness as absorption enhancers for poorly absorbable drugs compared with the conventional enhancers. They can enhance intestinal absorption of CF from all intestinal regions and they are effective at very low concentrations.

Colon-specific delivery and enhanced colonic absorption of [Asu(1,7)]-eel calcitonin using chitosan capsules containing various additives in rats.

The objective of this study was to estimate the colon-specific delivery of [Asu1,7]-eel calcitonin (ECT) using chitosan capsules in rats. The intestinal absorption of ECT was evaluated by measuring the plasma calcium levels after oral administration of the chitosan capsules containing ECT and different combinations of additives. The same combinations were investigated by an in situ absorption experiment prior to in vivo administration of capsules. A marked decrease in plasma calcium levels was observed following the oral administration of chitosan capsules containing ECT, S-nitroso-N-acetyl-dl-penicillamine (SNAP), sodium glycocholate, bacitracin and aprotinin (pharmacological availability (PA)% = 6.344%), as compared with capsules containing only ECT (PA% = 0.551%) or capsules containing ECT with SNAP only (PA% = 1.651%). The hypocalcemic effect started 6-8 h after oral administration of capsules and sustained for 24 h. These findings suggest that colon-specific delivery of ECT can be achieved using chitosan capsules and these additives may be useful for improving the colonic absorption of ECT in rats.

Nitric oxide donors can enhance the intestinal transport and absorption of insulin and [Asu(1,7)]-eel calcitonin in rats.

The characteristics of three NO donors, 3-(2-hydroxy-1-(1-methylethyl)-2-nitrosohydrazino)-1-propanamine (NOC5), N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC12) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) as absorption enhancers for peptide drugs were examined in rats using a modified Ussing chamber method and an in situ closed loop method. Insulin and [Asu(1,7)]-eel calcitonin (ECT) were used as a model drug to investigate the effectiveness of the tested enhancers. The NO donors significantly increased the in vitro permeability of insulin across all intestinal membranes. In general, the absorption enhancement effects of these NO donors were greater in the colon than those in the jejunum and ileum. Of these NO donors, SNAP was the most effective enhancer. Their effects were concentration-dependent over the range of 0.01 to 0.1 mM. However, 0.1 mM NO donors had almost the same effects as those at 1 mM concentration. The absorption-enhancing effects of the three NO donors were inhibited by the co-administration of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide, sodium salt (carboxy-PTIO), an NO scavenger, suggesting that NO might be responsible for the efficacy of NO donors. In the in situ closed loop experiments, the three enhancers significantly improved the pharmacological availability % (PA%) of insulin in the small and large intestine. Similar results were also obtained when NO donors were added to ECT solution by an in situ closed loop method. These results suggest that NO donors possess excellent effectiveness for the use as absorption enhancers of peptide drugs and they are very effective at lower concentrations compared to the conventional enhancers.

Improvement of absorption enhancing effects of n-dodecyl-beta-D-maltopyranoside by its colon-specific delivery using chitosan capsules.

In general, absorption enhancing effects of various absorption enhancers were greater in the large intestine than those in the small intestinal regions. Therefore, the effectiveness of absorption enhancers is expected to be remarkably observed, if these enhancers can be delivered to the large intestine with some poorly absorbable drugs after oral administration. In this study, therefore, we examined whether chitosan capsules were effective for the colon-specific delivery of a certain absorption enhancer and can improve the absorption enhancing action of the absorption enhancer after oral administration. 5(6)-Carboxyfluorescein (CF) was used as a model drug to investigate the site-dependent effectiveness of various absorption enhancers by an in situ closed loop method. Sodium glycocholate (NaGC), n-dodecyl-beta-d-maltopyranoside (LM), sodium salicylate (NaSal) and sodium caprate (NaCap) were used as models of absorption enhancers in this study. Overall, the absorption enhancing effects of these enhancers for intestinal absorption of CF were greater in the colon than those in the jejunum and the ileum. Especially, among these enhancers tested in this study, LM showed much greater absorption enhancing effect in the colon than in the jejunum and the ileum. Therefore, LM was selected as a model absorption enhancer to examine the effect of chitosan capsules on the absorption enhancing effect of LM. When CF and LM were orally administered to rats using chitosan capsules, the plasma concentration of CF was much higher than those in other dosage forms including solution and gelatin capsules. Therefore, chitosan capsules may be useful carriers for colon-specific delivery of LM, thereby increasing its absorption enhancing effect from the intestinal membranes.