Cationic starch derivatives as mucoadhesive and soluble excipients in drug delivery.

The aim of this study was to develop a novel mucoadhesive cationic polymer by introducing primary amino groups to the polymeric backbone of starch. This newly synthesized polymer should exhibit superior properties over chitosan regarding solubility, mucoadhesiveness and cytotoxicity. Increasing amounts of sodium periodate were used to cleave and oxidize vicinal diols under aldehyde formation obtaining three different degrees of modification. In a subsequent step, primary amines were introduced via reductive amination with ammonia. Degree of amination was examined with TNBS-assay and zeta potential measurements. Mucoadhesiveness was investigated by rotating cylinder, tensile studies and rheological measurements. Primary amino groups were successfully attached to the polymer, proven by zeta potential measurements and UV-spectroscopy. Depending on the amount of periodate used in the reaction, coupling rates of up to 514 µmol/g polymer were achieved. All synthesized derivatives showed 100% solubility in a pH range of 1-9. Aminated starch with the highest coupling rate of 514 µmol/g showed a 9.5-fold prolonged retention time on intestinal mucosa and a 2.7-fold higher total work of adhesion on the mucosal tissue compared to chitosan. Furthermore, cytotoxic examinations of all tested polymers showed only a low impact on cell viability after 24 h, whereby starch derivatives possessed even less cell toxic effects than chitosan. Summarizing these results, cationic starch derivatives seem to be promising excipients for mucosal drug delivery with superior properties compared to chitosan, the most examined cationic polymer.

N-Hydroxysulfosuccinimide Esters versus Thiomers: A Comparative Study Regarding Mucoadhesiveness.

The objective of the study was to compare poly(acrylic acid)- N-hydroxysulfosuccinimide reactive esters (PAA-Sulfo-NHS) and poly(acrylic acid)-cysteine conjugates (PAA-Cys) regarding their mucoadhesiveness. Polymer conjugates were synthesized in a water free environment and characterized by UV-vis spectroscopy and FTIR. Water uptake studies were performed, and the polymers were further examined for their mucoadhesive properties and cohesiveness using the rotating cylinder method. Tensile force measurements were conducted to define the strength of adhesion to porcine intestinal mucosa. Additionally, polymer-mucus mixtures were assessed for rheological synergism by measuring the increase in dynamic viscosity. Both modifications led to a prolonged adhesion time compared to unmodified PAA. Fast dissolution of PAA-Sulfo-NHS derivatives was monitored, whereas PAA-Cys tended to extensively swell while exhibiting high cohesive properties. Measurements of tensile force revealed up to 2.7-fold (PAA-Sulfo-NHS) and 2.3-fold (PAA-Cys) enhancement of the maximum detachment force and 7.6-fold (PAA-Sulfo-NHS) and 3.6-fold (PAA-Cys) increase in the total work of adhesion. Formation of a gel network between polymer and mucus was confirmed by a 10.8-fold (PAA-Sulfo-NHS) and 20.8-fold (PAA-Cys) increase in viscosity. Both types of polymers show high mucoadhesive properties due to the formation of covalent bonds with the mucus. As thiolated polymers are capable of forming stabilizing disulfide bonds within their polymeric network, they are advantageous over PAA-Sulfo-NHS.

Development of self-emulsifying drug delivery systems (SEDDS) for ciprofloxacin with improved mucus permeating properties.

The aim of this study was to develop a self-emulsifying drug delivery system (SEDDS) containing the fluoroquinolone antibiotic ciprofloxacin (CIP) exhibiting highly mucus permeating properties and antimicrobial activity in in vitro models. Various SEDDS formulations were developed and evaluated regarding droplet size, polydispersity index, zeta potential and formulation stability. Furthermore, SEDDS permeating properties were investigated in porcine intestinal mucus, as well as in cystic fibrosis (CF) sputum freshly collected from CF patients using Transwell® setup and single particle tracking (SPT), respectively. In order to evaluate antibacterial activity in an in vitro model against Staphylococcus aureus and other pathogens, minimum inhibitory concentrations (MIC) and time-kill curves were determined. In addition, in vitro release of ciprofloxacin and cytotoxicity studies were conducted. The preselected formulations F1 and F11 exhibited a mean droplet size of 79 nm and 25 nm, respectively, and a negative zeta potential. SEDDS containing CIP exhibit improved ability to permeate porcine intestinal mucus and CF sputum. After 4 h, F1-CIP formulation resulted in a 1.6 - fold and F11-CIP a 2.0 - fold higher amount of permeated ciprofloxacin through the sputum layer with respect to free CIP. Moreover, the antimicrobial activity of F11-CIP against S. aureus was higher than that of free CIP. According to these results, SEDDS formulations should be taken into consideration as promising delivery systems for the treatment of pulmonary infections accompanied by mucus dysfunction.

New perspectives of starch: Synthesis and in vitro assessment of novel thiolated mucoadhesive derivatives.

AIM: The purpose of this study was to develop a novel thiolated starch polymer with improved mucoadhesive properties by conjugation of cysteamine to starch as a natural polymer of restricted mucoadhesive properties. METHODS: Aldehyde substructures were integrated into starch via oxidative cleavage of vicinal diols by increasing amounts of sodium periodate followed by covalent attachment of cysteamine to oxidized starch via reductive amination. Thiol groups were quantified via Ellman's reaction and their impact on mucoadhesion was analyzed by rheological investigations, the rotating cylinder method and tensile studies on porcine mucosa. RESULTS: The total amount of immobilized thiol groups revealed a correlation between degree of oxidation and thiolation. Modified starch demonstrated an up to 1.66-fold increase in water uptake in comparison to native starch. Modification of starch resulted in greatly improved cohesive properties and improvement in mucoadhesion. Rheological investigations revealed a 2- to 4-fold rise in viscosity of mucus. Tensile studies revealed a linear correlation between degree of oxidation/thiolation and enhancement of maximum detachment force and total work adhesion. CONCLUSION: In terms of these results, thiolated starch is a new, promising, polymer in the field of mucoadhesive drug delivery systems.

Screening of anionic-modified polymers in terms of stability, disintegration, and swelling behavior.

This study aimed to screen the stability, disintegration, and swelling behavior of chemically modified anionic polymers. Investigated polymers were well-known and widely used staples of the pharmaceutical and medical field, namely, alginate (AL), carboxymethyl cellulose (CMC), polycarbophil (PC), and hyaluronic acid (HA). On the basis of amide bond formation between the carboxylic acid moieties of anionic polymers and the primary amino group of the modification ligand cysteine (CYS), the modified polymers were obtained. Unmodified polymers served as controls throughout all studies. With the Ellman's assay, modification degrees were determined of synthesized polymeric excipients. Stability assay in terms of erosion study at physiological conditions were performed. Moreover, water uptake of compressed polymeric discs were evaluated and further disintegration studies according to the USP were carried out to define the potential ranking. Results ranking figured out PCCYS > CMCCYS > HACYS > ALCYS in terms of water uptake capacity compared to respective controls. Cell viability assays on Caco-2 cell line as well as on RPMI 2650 (ATTC CCL30) proved modification not being harmful to those. Due to the results of this study, an intense screening of prominent anionic polymer derivate was performed in order to help the pharmaceutical research for the best choice of polymeric excipients for developments of controlled drug release systems.

Nasal drug delivery: Design of a novel mucoadhesive and in situ gelling polymer.

The aim of the present study was to establish a novel polymeric excipient for liquid nasal dosage forms exhibiting viscosity increasing properties, improved mucoadhesion and stability towards oxidation in solution. In order to achieve this goal, 2-mercaptonicotinic acid was first coupled to l-cysteine by disulfide exchange reaction and after purification directly attached to the polymeric backbone of xanthan gum by carbodiimide mediated amide bond formation. The resulting conjugate was characterized with respect to the amount of coupled ligand, the in situ gelling behavior, mucoadhesive properties and stability towards oxidation. Furthermore, the influence of preactivated polymers on ciliary beat frequency (CBF) of porcine nasal epithelial cells was investigated. Results showed, that 252.52±20.54µmol of the ligand was attached per gram polymer. No free thiol groups could be detected on the polymeric backbone indicating entire preactivation. Rheological investigations of polymer mucus mixtures revealed a 1.7-fold and 2.5-fold enhanced mucoadhesion of entirely preactivated xanthan (Xan-Cys-MNA) compared to thiolated xanthan (Xan-Cys) and unmodified xanthan (Xan). Tensile force evaluation reported a 2.87 and 5.11-fold higher total work of adhesion (TWA) as well as a 1.63 and 2.41-fold higher maximum detachement force of Xan-Cys-MNA compared to Xan-Cys and Xan. In the presence of H2O2 as an oxidizing agent Xan-Cys-MNA showed unlike Xan-Cys no increase in viscosity, indicating high stability towards oxidation. Addition of CaCl2 to Xan-Cys-MNA solutions caused a decrease in viscosity at nevertheless higher total viscosity. Results from CBF studies proved nasal safety for the novel conjugate. According to these results, entirely preactivated thiolated xanthan gum seems to be a promising excipient for nasal dosage forms in order to improve drug bioavailability.

Enhancing the efficiency of thiomers: Utilizing a highly mucoadhesive polymer as backbone for thiolation and preactivation.

The objective of this study was to develop a novel thiomer with enhanced mucoadhesive properties using a highly mucoadhesive polymeric backbone. Fixomer™ A-30 (poly(methacrylic acid-co-sodium acrylamidomethyl propane sulfonate)), exhibiting a mucoadhesive strength superior to that of all other polymers, was thiolated by conjugation with l-cysteine and furthermore preactivated with 2-mercaptonicotinic acid (MNA). The resulting derivatives Fix-SH and Fix-S-MNA exhibited coupling rates of 755µmol thiol groups and 304µmol MNA per gram polymer, respectively. The mucoadhesive profile was evaluated with three different methods: tensile studies, rotating cylinder and rheological synergism. In tensile studies, a total work of adhesion of above 500µJ was determined for the unmodified polymer that increased to around 750µJ after thiolation and around 1500µJ after preactivation. The adhesion time of Fix-SH on the rotating cylinder was 3.7-fold and that of Fix-S-MNA 6.8-fold longer compared to the unmodified polymer. A rheological synergism was observed for the unmodified polymer as well as the derivatives with a non-significant difference for Fix-SH but a 5.44-fold improvement for Fix-S-MNA. Fix-S-MNA showed a significantly improved swelling behavior with a water-uptake up to the 30-fold of its initial weight over >50h whereas thiolation showed only slight improvements. Derivatization had no significant influence on cell viability. According to the results, Fix-S-MNA seems to be a suitable polymer for mucoadhesive drug delivery systems.

Design, modification and in vitro evaluation of pectin's bucco-adhesiveness.

AIM: It was the aim of this study to synthesize pectin (PEC) with sulfhydryl groups and evaluate its suitability in buccal application. MATERIALS & METHODS: Native PEC was chemically modified by covalent attachment of sulfhydryl-bearing cysteine (CYS). Stability assays in form of water uptake behavior and erosion study were performed. Additionally, mucoadhesive study on buccal mucosa was performed. RESULTS: Pectin-cysteine (PECCYS) was successfully synthesized as proved by IR and Ellman's assay exhibiting 436.59 ± 127.87 µmol thiol groups per gram polymer. Stability assay showed that PECCYS revealed a 2.27-fold improved water uptake and mucoadhesiveness augmented 3.75-fold in comparison to unmodified PEC. CONCLUSION: PECCYS might be a future suitable excipient for buccal adhesive application.

Next generation of buccadhesive excipient: Preactivated carboxymethyl cellulose.

AIM: Assessment of preactivated carboxymethyl cellulose as potential excipient for buccal drug delivery. METHODS: Firstly, carboxymethyl cellulose (CMC) and cysteine (SH) were covalently coupled via amide bond formation to obtain thiolated carboxymethyl cellulose (CMC-SH). Further, preactivated carboxymethyl cellulose (CMC-S-S-MNA) was obtained by preactivation with 2-mercaptonicotinic acid (MNA). Sulforhodamine 101 (SRH101) was used as a model drug for permeation study through buccal mucosa. CMC-S-S-MNA was evaluated with respect to mucoadhesive and permeation enhancing effect and cytotoxicity. RESULTS: Thiolated carboxymethyl cellulose exhibited a total amount of 112.46 ± 0.46 thiol groups. CMC-S-S-MNA exhibited around 50% of preactivated thiol groups. The preactivated polymer showed no toxic effect. Furthermore, compared to unmodified CMC, CMC-S-S-MNA revealed 3.0-fold improved mucoadhesive properties according to the rotating cylinder method and 8.8-fold enhancement in mucoadhesiveness by tensile assay, respectively. CONCLUSION: Preactivated carboxymethyl cellulose fulfills the requirements as potential excipient of being mucoadhesive and permeation enhancing for the buccal drug delivery.

Preactivated thiolated nanoparticles: A novel mucoadhesive dosage form.

Within this study a novel form of mucoadhesive nanoparticles (NPs) exhibiting a prolonged residence time on mucosal tissues was developed. In order to achieve this goal a new thiomer was synthesized by the covalent attachment of the amino acid l-cysteine ethyl ester to poly(acrylic acid) (100 kDa). The free thiol groups were in the following preactivated with the aromatic thiol bearing ligand 2-mercaptonicotinic acid (2-MNA) and the amount of coupled l-cysteine ethyl ester as well as the amount of attached 2-MNA was determined. Based on this, preactivated thiomer NPs were prepared by ionic gelation with polyethylenimine (PEI). The resulting NPs were characterized regarding size and zeta potential. Furthermore their mucoadhesive properties were investigated via rheological measurements with porcine intestinal mucus and via determination of the particles' mucosal residence time. Results showed that 1666.74 µmol l-cysteine ethyl ester and 603.07 µmol 2-MNA could be attached per gram polymer. NPs were in a size range of 112.67-252.84 nm exhibiting a zeta potential of -29 mV. Thiolated NPs only led to a 2-fold increase in mucus viscosity whereas preactivated NPs showed a 6-fold higher mucus viscosity than unmodified NPs. The mucosal residence time of thiolated NPs was 1.6-fold prolonged and that of preactivated NPs even 4.4-fold higher compared to unmodified particles. Accordingly, preactivated thiolated NPs providing a prolonged residence time on mucosal membranes could be a promising dosage form for various applications.

Self-administered procedural analgesia using nitrous oxide/oxygen (50:50) in the pediatric surgery emergency room: effectiveness and limitations.

INTRODUCTION: Minor surgical interventions in children are often at times challenging due to the lack of cooperation by the child. Procedural sedation and analgesia is often appropriate, but unpleasant or painful applications of medication add additional discomfort to the child. A mixture of nitrous oxide (N2O)/oxygen (O2) in a ratio of 50:50, functioning as an inhalational sedative analgesic, may be a viable alternative, in particular in an emergency care setting because such mixtures require no fasting period and are self-administered. Therefore, in this study we investigated the feasibility and the effectiveness of N2O/O2 (50:50) as a sedative analgesic when performing minor surgical procedures. PATIENTS AND METHODS: Procedural sedation and analgesia with an N2O/O2 (50:50) mixture applied during minor surgical procedures were prospectively evaluated over 2.5 years in a major pediatric hospital in Germany. Indications for sedation were either minor painful interventions, the injection of a local anesthetic, or a digital block in an emergency care setting. Diagnosis, type of surgery, inhalation time, complications, side effects, pain scores, and the child's behavioral reaction were assessed. RESULTS: A N2O/O2 (50:50) mixture was administered in 210 children, ages 2.7 to 16.5 years (mean 9.0 years). Three treatments were terminated because of lack of compliance, nausea, or dizziness. No other side effects were encountered. During the intervention, 80.5% of all patients were pain free, and 81.9% were relaxed and calm. A higher rate of insufficient pain control was observed when the indication was an injection of a digital block or a reposition of fractures and dislocations. CONCLUSIONS: The use of self-administered N2O/O2 (50:50) mixture for minor painful procedures in children is safe and adequate pain control can be achieved in most cases. The benefits of this approach for the child and its parents are its good acceptance and adequate pain control. The benefit for the health care provider is the lack of a fasting period before administration, good anxiolysis at minimum sedation, and a cooperative patient. Limitations are unsatisfying analgesia in some cases. Though not found in our study, potentially serious adverse events are a possibility and standard safety guidelines for minimal sedation should always be applied.