In situ ophthalmic gel of ciprofloxacin hydrochloride for once a day sustained delivery

This article focuses on preparation and evaluation of a once a day ophthalmic delivery system for ciprofloxacin hydrochloride based on the concept of pH-triggered in situ gelation. The in situ gelling system involves the use of polyacrylic acid (Carbopol® 980NF) as a phase transition polymer, hydroxypropyl methylcellulose (Methocel® K100LV) as a release retardant, and ion exchange resin as a complexing agent. Ciprofloxacin hydrochloride was complexed with ion exchange resin to avoid incompatibility between drug and polyacrylic acid. The developed formulation was stable, and nonirritant to rabbit eyes and in vitro drug release was found to be around 98% over a period of 24 hours.     

Ophthalmic delivery of ciprofloxacin hydrochloride from different polymer formulations: in vitro and in vivo studies

Reservoir-type ocular inserts were fabricated using sodium alginate containing ciprofloxacin hydrochloride as the core (drug reservoir) that was sandwiched between the Eudragit and/or polyvinylacetate films. Ocular inserts were packaged in aluminium foil and sterilized by gamma radiation. These were tested for sterility as per British Pharmacopoeia (BP). Ocular inserts were evaluated for in vitro release rate studies, microbial efficacy, in vivo release studies, efficacy against induced bacterial conjunctivitis in rabbit's eyes, concentration in the aqueous humor, and stability studies as per the International Conference on Harmonization (ICH) guidelines. Ocular inserts passed the test for sterility. They showed zero-order release of the drug in the in vitro and in vivo release studies over a period of 120 hr. The drug was found to be active against selected microorganisms as was proved by microbial efficacy studies. A high correlation coefficient was found between in vitro and in vivo release rate studies. Better improvement was observed in artificially induced bacterial conjunctivitis in rabbit's eyes, compared with marketed eye drops and placebo. Drug concentration in the aqueous humor was found above Minimum Inhibitory Concentration (MIC-90) against selected microorganisms. Shelf-life of the product was found to be more than 2 years.     

Anti-adhesive effect of poloxamer-based thermo-sensitive sol-gel in rabbit laminectomy model

Poloxamer-based thermo-sensitive sol-gel has been developed to reduce the incidence of postoperative scar formation at the laminectomy site. The purpose of this study was to evaluate the anti-adhesive effect of poloxamer based thermo-sensitive sol-gel compared to hyaluronate based solution after laminectomy, using a rabbit model. A thermo-sensitive anti-adhesive with a property of sol-gel transition was manufactured by a physical mixture of Poloxamer188/407, Chitosan and Gelatin. The viscosity in different temperatures was assessed. 72 adult New Zealand rabbits underwent lumbar laminectomy and were randomly divided into experimental (treated with the newly developed agent), positive (treated with hyaluronate based solution), and negative control groups. Each group was subdivided into 1 and 4-week subgroups. Gross and histological evaluations were performed to assess the extent of epidural adhesion. The experimental group showed significantly higher viscosity compared to the positive control group and showed a significant increase of viscosity as the temperature increased. Gross evaluation showed no statistically significant differences between the 1- and 4-week subgroups. However, histologic evaluation showed significant differences both in 1- and 4-week subgroups. Although the 4-week histologic results of the experimental and the positive control subgroups showed no significant difference, both subgroups revealed higher value compared to the negative control subgroup with regard to the ratio of adhesion less than 50?%. The new poloxamer based thermo-sensitive agent showed superior efficacy over the hyaluronate based agent at 1?week postoperatively. At 4?weeks postoperatively, there were no statistically significant differences between the two agents, although both showed efficacy over the sham group.     

Development of dorzolamide hydrochloride in situ gel nanoemulsion for ocular delivery

Background: Several in situ gel-forming systems have been developed to prolong the precorneal residence time of a drug and to improve ocular bioavailability. Poloxamer 407 with its thermoreversible gelation and surface active properties was utilized to formulate a novel dorzolamide hydrochloride in situ gel nanoemulsion (NE) delivery system for ocular use. Objective: Improvement of both ocular bioavailability and duration of action for dorzolamide hydrochloride was the aim of this study. Methods: Physicochemical properties, in vitro drug release studies and biological evaluation of the prepared NEs were investigated. Results: The optimum formulation of in situ gel NE consisted of Triacetin (7.80%), Poloxamer 407 (13.65%), Poloxamer 188 (3.41%), Miranol C2M (4.55%), and water (70.59%). Biological evaluation of the designed dorzolamide formulation on normotensive albino rabbits indicated that this formulation had better biological performance, faster onset of action, and prolonged effect relative to either drug solution or the market product. The formula showed a superior pharmacodynamic activity compared to the in situ gel dorzolamide eye drops. This indicated the effectiveness of the in situ gel properties of poloxamer 407, besides formulating the drug in an NE form for improving the therapeutic efficacy of the drug. Conclusion: These results demonstrate the superiority of in situ gel NE to conventional ocular eye drops and in situ gels to enhance ocular drug bioavailability.     

Design and evaluation of soluble ocular drug insert for controlled release of ciprofloxacin hydrochloride

Purpose: Soluble ocular inserts of ciprofloxacin hydrochloride were prepared with the aim of achieving once a day administration. Design: Drug reservoir was prepared using natural hydrophilic polymer viz. gelatin while rate-controlling membrane was prepared using hydrophobic ethyl cellulose. Ocular inserts were evaluated for their physicochemical parameters like thickness, weight uniformity, drug content, percent moisture loss, and percent moisture absorption. The in vitro drug release studies were carried out using Bi-chambered donar receiver compartment model. Since targeted prolong release was observed in formulation CF2 and CF5, these formulations were further subjected to in vivo drug release study using rabbits as an animal model. In vitro drug release kinetic data was treated according to Zero, First, and Higuchi kinetics to access the mechanism of drug release. Results: Correlation between in vitro and in vivo drug release was found to be strong revealing the efficacy of the formulation. Conclusion: Formulation CF5 has achieved target of present study such as increase residence time, prolong drug release, reduction in frequency of administration, and, thus may improve the patient compliance.     

Preparation and biocompatibility study of in situ forming polymer implants in rat brains

We describe the development of polymer implants that were designed to solidify once injected into rat brains. These implants comprised of glycofurol and copolymers of d,l-lactide (LA), ε-caprolactone and poly(ethylene glycol) (PLECs). Scanning electron microscopy (SEM) and gel permeation chromatography (GPC) showed that the extent of implant degradation was increased with LA content in copolymers. SEM analysis revealed the formation of porosity on implant surface as the degradation proceeds. PLEC with 19.3% mole of LA was chosen to inject in rat brains at the volume of 10, 25 and 40 μl. Body weights, hematological and histopathological data of rats treated with implants were evaluated on day 3, 6, 14, 30 and 45 after the injection. Polymer solution at the injection volume of 10 μl were tolerated relatively well compared to those of 25 and 40 μl as confirmed by higher body weight and healing action (fibrosis tissue) 30 days after treatment. The results from this study suggest a possible application as drug delivery systems that can bypass the blood brain barrier.     

Formulation and evaluation of injectable in situ forming microparticles for sustained delivery of lornoxicam

The objective of this study is to formulate biodegradable in situ microparticles (ISM) containing lornoxicam for post-operative and arthritic pain management. ISM emulsions were prepared according to 2⁵ full factorial experimental design to investigate the influence of formulation variables on the release profile of the drug. The independent variables studied are the polymer type, polymer inherent viscosity, polymer concentration, oil type and polymer:oil ratio. In vitro drug release, microscopical examination, particle size determination and syringeability measurement were selected as dependent variables. The effect of γ-sterilization on the prepared formulae was also examined. The prepared formulae showed extended drug release over two weeks, and flow time below 5?s/ml. Scanning electron microscope revealed that the prepared microparticles were spherical in shape, with diameter ranging from 3.45 to 22.78?µm. In vivo pharmacokinetic evaluation of two selected optimum formulations in rabbits showed prolonged drug absorption indicated by delayed T_max and the extended mean residence time. In conclusion, the prepared injectable ISM could be a promising approach for providing extended delivery of lornoxicam with low initial burst effect.     

Rapidly in situ forming adhesive hydrogel based on a PEG-maleimide modified polypeptide through Michael addition

Polyethylene glycol-maleimide modified ε-polylysine (EPL-PEG-MAL) with a unique comb-shaped structure was designed and used as a novel crosslinker for thiolated chitosan (CSS). Novel polysaccharide/polypeptide bionic hydrogels based on CSS and EPL-PEG-MAL could form rapidly in situ within 1 min via Michael addition under physiological conditions. Rheological studies showed that introduction of PEG can dramatically improve the storage modulus (G′) of the hydrogels and the optimal hydrogel system showed superior G′ of 1,614 Pa. The maximum adhesion strength reached 148 kPa, six times higher than that of fibrin glue. Cytotoxicity test indicated that the hydrogel is nontoxic toward growth of L929 cells. Gelation time, swelling ratio, storage modulus and adhesion strength of the hydrogels can be modulated by the content of PEG-maleimide, CSS concentration and molar ratio of maleimide group to thiol group. Benefiting from the fast gelation behaviors, desirable mechanical properties, relatively high adhesive performance and no cytotoxicity, these hydrogels have the potential applications as promising biomaterials for tissue adhesion and sealing.     

An in situ synthesis of mesoporous SBA-16/hydroxyapatite for ciprofloxacin release: in vitro stability and cytocompatibility studies

The present work developed a biomaterial (HA/SBA-16) based on the growth of calcium phosphate (HA) particles within an organized silica structure (SBA-16) to evaluate its application as a drug delivery system. The samples were charged with ciprofloxacin as a model drug and in vitro release assays were carried out. The samples were characterized by elemental analysis (CHN), Fourier transform infrared spectroscopy, nitrogen adsorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), small angle X-ray scattering (SAXS) and X-ray diffraction. The results obtained by TEM, SEM and SAXS reveal a well-defined cubic arrangement of a uniform spherical mesoporous structure, an intrinsic characteristic of these materials, which indicated that SBA-16 and HA/SBA-16 could potentially encapsulate bioactive molecules by means of ordered mesopores. It was found that both surface interaction and pore volume affect the rate and amount of ciprofloxacin released from the mesoporous materials. In vitro assays were performed to evaluate the adhesion, viability, and growth behavior of human adipose tissue-derived stem cells (hADSC) on SBA-16 and HA/SBA-16 nanocomposites to verify their potential as a scaffold for application in bone–tissue engineering using MTT assay and alkaline phosphatase activity tests. The results showed that the materials are promising systems for bone repair, providing a good environment for the adhesion and proliferation of rat mesenchymal stem cells and hADSC in vitro.     

C(60) reduces the flammability of polypropylene nanocomposites by in situ forming a gelled-ball network

The thermal and flame retardancy properties of polypropylene/fullerene (PP/C(60)) nanocomposites were investigated by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and cone calorimetry with the C(60) loading varied from 0.5 to 2% by weight. Dispersion of C(60) in the PP matrix was characterized by transmission electron microscopy (TEM) and optical microscopy (OM). TGA and DSC results showed that the presence of C(60) could remarkably enhance the thermal property and cone calorimeter measurements suggested that C(60) could to some extent reduce the flammability of PP, with a significant reduction in peak heat release rate and a much longer time to ignition. Furthermore, the larger the loading level of C(60), the better the flame retardancy property of PP/C(60) nanocomposites. The flame retardation mechanism and corresponding model were proposed with the help of rheological measurements, TEM and x-ray diffraction. C(60) reduced the flammability of PP by trapping free radicals in the gas phase and in situ forming a gelled-ball crosslink network to improve the flame retardancy of PP in the condensed phase. Finally, this suggested mechanism was supported by the results of advanced rheological extended systems (ARES), gel content, infrared spectrum, OM, and atomic force microscopy (AFM) measurements.     

Nanoparticle-enhanced thermoluminescence in silica gels

The results of transmission electron microscopy and thermoluminescence (TL) studies in silica samples containing Fe and Cu nanosized particles show an important enhancement of their TL response when compared with known reports for pure silica samples. The effect of surface electronic states in the nanoparticles, interacting with the matrix, may be responsible for this new size-dependent effect.     

Living bacteria in silica gels

The encapsulation of enzymes within silica gels has been extensively studied during the past decade for the design of biosensors and bioreactors. Yeast spores and bacteria have also been recently immobilized within silica gels where they retain their enzymatic activity, but the problem of the long-term viability of whole cells in an inorganic matrix has never been fully addressed. It is a real challenge for the development of sol-gel processes. Generic tests have been performed to check the viability of Escherichia coli bacteria in silica gels. Surprisingly, more bacteria remain culturable in the gel than in an aqueous suspension. The metabolic activity of the bacteria towards glycolysis decreases slowly, but half of the bacteria are still viable after one month. When confined within a mineral environment, bacteria do not form colonies. The exchange of chemical signals between isolated bacteria rather than aggregates can then be studied, a point that could be very important for 'quorum sensing'.     

Ocular permeability of pirenzepine hydrochloride enhanced by methoxy poly(ethylene glycol)-poly(D, L-lactide) block copolymer

Methoxy poly(ethylene glycol)-poly(D,L-lactide) block copolymer was tested as an ocular permeation enhancer for pirenzepine hydrochloride. The block copolymers with the methoxy poly(ethylene glycol) to poly(D,L-lactide) weight ratio of 80/20, 50/50, 40/60 were synthesized by a ring-opening polymerization procedure. In vitro transcorneal experiments demonstrated that the block copolymer 80/20 significantly enhanced the transcorneal permeation of pirenzepine at the mass ratio of 1/1.4 (pirenzepine hydrochloride/copolymer). Interaction between pirenzepine and copolymer was identified by infrared spectroscopy analysis and dialysis experiments. Ocular pharmacokinetics of pirenzepine/copolymer preparation by in vivo instillation experiments confirmed that block copolymer could enhance the ocular penetration of pirenzepine. Ocular chronic toxicity experiments of block copolymer and pirenzepine/copolymer preparation were studied on rabbits, and no significant toxicity in both groups was observed within 9 months. It could conclude that pirenzepine/copolymer preparation is effective and safe in ocular delivery of pirenzepine.     

Experimental investigations and optimization of forming force in incremental sheet forming

Incremental sheet forming process has been proved to be quiet suitable and economical for job and batch type production, which exempts expensive and complex tooling for sheet forming. Investigation of forming forces becomes important for selecting the appropriate hardware and optimal process parameters in order to assure perfection and precision of process. Moreover, lack of available knowledge regarding the process parameters makes the process limited for industrial applications. This research paper aims at finding out effects of different input factors on forming forces in single-point incremental forming (SPIF) process. For operation sustainability and hardware safety, it becomes critical to optimize forming forces for a given set of factors to form a particular shape. In this study, optimization of input factors has been performed to produce conical frustums with helical tool path using Taguchi analysis as design of experiment (DOE) and analysis of variance (ANOVA). The optimal experimental conditions for forming forces have been calculated as sheet thickness (0.8 mm), step size (0.2 mm), tool diameter (7.52 mm), tool shape (hemispherical), spindle speed (1000 rpm), feed rate (1000 mm/min) and wall angle (50^o). Effects of tool shape and viscosity of lubricants have also been investigated. An intensive understanding of the mechanism of forming forces has been presented, which shows that force trend after peak values depends upon instant input factors that can be categorized as a safe, severe and crucial set of parameters.     

UPLC测定黄连中盐酸小檗碱和盐酸巴马汀的含量

建立UPLC测定黄连中盐酸小檗碱和盐酸巴马汀含量的方法。采用ACQUITY UPLC BEH-C18色谱柱(2.1mm×50 mm×1.7μm),以乙腈-0.05mol/L磷酸二氢钾溶液为流动相,梯度洗脱,流速为0.2 mL/min,检测波长为350 nm。结果表明盐酸小檗碱和盐酸巴马汀分别在0.037 2～0.297 6μg/mL,0.008 2～0.065 6μg/mL的浓度范围内均有良好的线性关系(r=0.9999),回收率均大于95%,RSD均小于2%。该方法快速、准确、重现性好,可用于测定黄连中盐酸小檗碱和盐酸巴马汀的含量。     

Origins of phase separation in gels

The phenomenon of phase separation in gels is established both theoretically and experimentally. The origin is attributed to the unfavourable free energy of mixing and/or the inherent polymerization and condensation of polymer species in gels.     

Hydroxyapatite pattern formation in PVA gels

Sodium hydroxide solution was allowed to diffuse from the edge of an acidic poly(vinyl alcohol) gel sheet containing dissolved calcium and phosphate ions, and calcium phosphate was observed to precipitate as the pH rose. The precipitation pattern changed depending on the solute concentration near the reaction front; precipitate “walls” were formed in areas in which the calcium phosphate concentration was higher or the sodium hydroxide concentration was lower than the conditions for homogeneous precipitation, and within a very limited concentration combination of calcium phosphate and sodium hydroxide, a regular stripe pattern with a pitch of about 100 μm was formed. The calcium phosphate precipitate obtained was a single phase of hydroxyapatite. It was also found that apatite ceramic sheets with periodic porous structures or with undulate patterns could be manufactured by sintering gels with stripe patterns.     

Long-term sustained-released in situ gels of a water-insoluble drug amphotericin B for mycotic arthritis intra-articular administration: preparation,in vitro and in vivo evaluation

Amphotericin B (AMB) was often used in intra-articular injection administration for fungal arthritis, because it could often bring a satisfactory therapeutic efficacy and a minimum systemic toxic side effect. However, because of the multiple operations and the frequent injections, the compliance of the patients was bad. Therefore, to develop a long-term sustained-released preparation of AMB for mycotic arthritis intra-articular administration is of great significance. The purpose of present study was to develop a long-term sustained-released in situ gel of a water-insoluble drug AMB for mycotic arthritis intra-articular administration. Based on the evaluations of the in vitro properties of the formulations, the formulation containing 10% (w/w) ethanol, 15% (w/w) PG, 0.75% (w/w) HA, 5% (w/w) purified soybean oil, 0.03% (w/w) α-tocopherol, 15% (w/w) water and 55% (w/w) glyceryl monooleate was selected as a suitable intra-articular injectable in situ gel drug delivery system for water-insoluble drug AMB. Furthermore, the results of the in vivo study on rabbits showed that the selected formulation was a safe and effective long-term sustained-released intra-articular injectable AMB preparation. Therefore, the presented in situ AMB gel could reduce the frequency of the administration in the AMB treatment of fungal arthritis, and then would get a good patient compliance.