Preparation of ketoprofen‐loaded high‐molecular‐weight poly(vinyl alcohol) gels

High‐molecular‐weight atactic poly(vinyl alcohol) (a‐PVA) gels loaded with (R,S)‐2‐(3‐benzoylphenyl)propionic acid (ketoprofen) were prepared from 5, 6, 7, and 8 g/dL solutions of a‐PVA with a number‐average degree of polymerization of 4000 in an ethylene glycol/water mixture with an aging method to identify the effect of the initial polymer concentration on the swelling behavior, morphology, and thermal properties of a‐PVA gels. Then, the release behavior of ketoprofen from a‐PVA gels was investigated. As the polymer concentration decreased, the ability for network formation decreased, and the degree of swelling of the a‐PVA gels increased. In addition, the enthalpy increased with an increase in the a‐PVA concentration, but the melting temperatures of the gels prepared at different initial polymer concentrations were the same; this indicated that tighter gel networks would be formed by a higher polymer chain density. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Ketoprofen Spray-dried Microspheres Based on Eudragit® RS and RL: Study of the Manufacturing Parameters

The preparation of ketoprofen spray-dried microspheres can be affected by the long drug recrystallization time. Polymer type and drug–polymer ratio as well as manufacturing parameters affect the preparation. The purpose of this work was to evaluate the possibility to obtain ketoprofen spray-dried microspheres using the Eudragit® RS and RL; the influence of the spray-drying parameters on morphology, dimension, and physical stability of microspheres was studied. Ketoprofen microspheres based on Eudragit® blend can be prepared by spray-drying and the nebulization parameters do not influence significantly particle properties; nevertheless, they can be affected by drying and storage methods. No effect of the container material is found.     

一种新颖的酮洛芬合成工艺

针对传统工艺时间较长,容易产生自身缩合副产物的问题,本工艺以腈乙基二苯甲酮为原料,经碱性条件下水解得酮洛芬。反应时间从10h缩短为1h,副反应少,原料转化率高,产品收率达99%以上。     

Characterization of gamma irradiated concentrated aqueous solutions of chitosan/sodium alginate blends and their drug uptake‐release characters

Blends films based on different ratios of concentrated aqueous solutions of chitosan (CS) and sodium alginate (AG) in the presence of 1% of glutaraldehyde, as a cross‐linking agent for chitosan, were prepared by solution casting and then exposed to gamma irradiation. The formed blends were characterized by IR spectroscopic analysis, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The uptake‐release properties of CS/AG blends, taking ketoprofen as an example for drug, were also investigated. DSC thermograms of CS/AG blends revealed good miscibility was sustained between CS and AG. The water uptake and gel content of CS/AG blends was found to decrease by increasing the ratio of AG in the initial solution. The IR spectra indicated the formation of cross‐linking and hydrogen bonding, while the TGA study showed that the CS/AG blends displayed higher thermal stability than pure CS polymer. Based on Fick's law, it was demonstrated that the main parameters affecting the release of ketoprofen drug from the CS/AG blend hydrogels were composition and pH. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

酮基布洛芬生产工艺研究与改进

分析了酮基布洛芬原生产工艺,重点对甲基化反应和酰化-傅克反应过程进行了研究与改进:以高选择性单甲基化试剂(CH_3O)_2CO代替(CH_3O)_2SO_2,实现了单基化反应;傅克反应过程用苯-SOCl_2共沸带出酰氯物中的SOCl_2,避免了副产物二苯亚砜的生成.工艺改进后,总收率比原有工艺的总收率提高了28.2%以上.     

Synthesis and characterization of poly(N-vinylcaprolactam)-based spray-dried microparticles exhibiting temperature and pH-sensitive properties for controlled release of ketoprofen

Poly(N-vinylcaprolactam) (PNVCL) and poly(N-vinylcaprolactam-co-acrylic acid) (poly(NVCL-co-AA)) were synthesized by solution-free radical polymerization and displayed thermo-responsive behavior, with lower critical solution temperatures (LCSTs) of 35?°C and 39?°C, respectively. The incorporation of AA unities made the poly(NVCL-co-AA) sensitive to both pH and temperature. They were exploited in this work in preparing microparticles loaded with ketoprofen via spray-drying to modulate the drug release rate by changing pH or temperature. The interaction between polymer and drug was studied using X-ray diffractometry, Raman spectrometry and scanning electron microscopy (SEM). The biocompatibility of pure polymers, free ketoprofen as well as the spray-dried particles was demonstrated in vitro by low cytotoxicity and a lack of nitric oxide production in macrophages at concentrations as high as 100?µg/ml. The release profile of ketoprofen was evaluated by in vitro assays at different temperatures and pH values. Drug diffusion out of PNVCL’s hydrated polymer network is increased at temperatures below the LCST. However, when poly(NVCL-co-AA) was used as the matrix, the release of ketoprofen was primarily controlled by the pH of the medium. These results indicated that PNVCL and the novel poly(NVCL-co-AA) could be promising candidates for pH and temperature-responsive drug delivery systems.     

以葡辛胺为拆分剂拆分酮基布洛芬

The process of resolution of racemic ketoprofen using n-octyl-d-glucamine as an optical resolution agent was investigated. The process consists of preparation of the diastereomer salt of ketoprofen with n-octyl-d-glucamine, liberation of S-（＋）-ketoprofen from its diastereomer salt and recovery of the remaining ketoprofen and n-octyl-d- glucamine. The suitable conditions for preparation of the diastereomer salt were methanol and ethyl acetate （1：1 by volume） as the solvent, the ratio of solvent volume to ketoprofen mass at 8 ml：1 g, and the molar ratio of ketoprofen to n-octyl-d-glucamine at 1：1. The preferred approach to liberate S-（＋）-ketoprofen from its diastereomer salt was alkali dissolution, acid adjustment and ethyl acetate extraction. Racemization of the recovered ketoprofen could be achieved by reacting the recovered ketoprofen with 10% NaOH at 507kPa for 6h. The recovered n-octyl-d- glucamine could be refined by acid dissolution and alkali adjustment. S-（＋）-ketoprofen can be obtained with high optical purity and yield, showing that the present process is a practical and efficient one which can be used in industrial scale for preparation of S-（＋）-ketoprofen.     

Ketoprofen affects the mammary immune response in dairy cows in vivo and in vitro

Nonsteroidal anti-inflammatory drugs are commonly administered parenterally in addition to antimicrobial mastitis therapy to increase the well-being of the diseased animal. As mastitis is usually a localized infection of mammary tissue, we tested the hypothesis that a local administration of nonsteroidal anti-inflammatory drugs through the teat canal could have anti-inflammatory effects on the affected area. We investigated the effects of intramammarily administered ketoprofen (KET) during an LPS-induced immune response on somatic cell count (SCC) and blood–milk barrier integrity. In addition, we investigated the effects of KET on the mRNA abundance of immune factors and their prostaglandin E2 secretion in primary bovine mammary epithelial cells in vitro. Six cows received 0.2 µg of LPS (serotype O26:B6) together with 50 mg of KET into one quarter and LPS only in the opposing quarter. The increase of SCC and of serum albumin (SA) and IgG concentrations and the increase of lactate dehydrogenase (LDH) activity in milk induced by LPS were lower in quarters that received KET in addition. In 3 cows, intramammary KET (50 mg) without additional LPS did not affect SCC, SA, IgG, and LDH in milk. Effects of KET on the immune response of mammary epithelial cells in vitro were investigated in cells from 3 cows challenged with or without LPS (0.2 µg/mL) and with or without additional KET in 2 concentrations (1.25 or 2.5 mg/mL). Ketoprofen reduced the LPS-induced increase of mRNA abundance of tumor necrosis factor α, IL-8, serum amyloid A, and cyclooxygenase-2. The mRNA abundance of cyclooxygenase-1 and prostaglandin E synthase was reduced in cells without LPS challenge by addition of KET at 2.5 mg/mL. Furthermore, the LPS-induced secretion of prostaglandin E2 of mammary epithelial cells into the supernatant could not be detected if KET was added. The results demonstrate that intramammary KET diminishes the increase of SCC and reduces the impairment of the blood–milk barrier (based on SA and LDH in milk), leading to a reduced IgG concentration in milk during LPS-induced mastitis. In mammary epithelial cells, KET limits the expression of several immune factors that are increased during an immune response. In summary, intramammary administration of KET reduces the inflammatory response in the mammary gland. However, it remains unclear whether the inhibited transfer of immune cells and IgG from blood into milk after KET administration would reduce the success of the immune defense in infectious mastitis.     

Fabrication of size‐controllable mPEG‐decorated microparticles conjugating optically active ketoprofen based on self‐assembly of amphiphilic random copolymers

Novel size‐controllable mPEG‐decorated polymeric microparticles binding optically active ketoprofen were successfully fabricated based on chemoenzymatic synthesis and self‐assembly of amphiphilic random polymer–ketoprofen conjugates with mPEG and (S)‐ketoprofen as pendants. A series of mPEG₃₅₀‐ or mPEG₁₀₀₀‐functionalized amphiphilic random polymer–ketoprofen conjugates with drug loading capacity from 16.5% to 73.2% were easily prepared by combining enzymatic resolution with radical polymerization and characterized by Fourier Transform Infrared spectroscopy, ¹H‐NMR, and gel permeation chromatography. The formation of aggregates from the amphiphilic random polymer–ketoprofen conjugates was investigated by ultraviolet‐visible absorption spectra using pyrene as the guest molecule. Transmission electron microscopy measurement revealed that the self‐assemblies were well dispersed as spherical microparticles. The size of the self‐assemblies could be widely tuned by varying the length of mPEG chains and the content of ketoprofen in the synthetic polymer–ketoprofen conjugates, and a series of mPEG‐decorated (S)‐ketoprofen‐bound polymeric microparticles with average radius from 70 nm to 1.1 μm were obtained. The successful preparation of the microparticles containing (S)‐ketoprofen provided a new strategy for the design and fabrication of optically active drug delivery systems. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Short communication: A comparison of 2 nonsteroidal antiinflammatory drugs following the first stage of a 2-stage fistulation surgery in dry dairy cows

Postoperative pain and its management following fistulation surgery in cattle are poorly understood. The purpose of this study was to compare 2 nonsteroidal antiinflammatory drugs (NSAID) as potential postoperative pain management treatments following the first stage of a 2-stage fistulation surgery. A randomized complete block design trial was conducted in dry Holstein cows (n = 10) following fistulation surgery. Ketoprofen (3 mg/kg of body weight i.m.) was administered on the day of surgery and 24 h later, whereas meloxicam (0.5 mg/kg of body weight s.c.) was administered once only on the day of surgery. Outcomes evaluated at 0, 2, 9, 24, 26, and 33 h postsurgery were heart rate, respiration rate, rectal temperature, and infrared temperature around the surgical site. Outcomes evaluated on the day of surgery and d 1 following surgery and compared with the average for the 4 d before surgery were lying activity (total lying time, total time spent lying on the left side, and percentage of time lying on the left side) and feed intake. A difference was observed in dry matter intake on d 1 but this effect was not different on d 0 compared with presurgical averages. A difference was observed in time spent lying on the left side and a difference was observed in heart rate following the first stage of fistulation surgery compared with presurgical averages. The infrared temperature readings around the surgical site were significantly greater in the hours following surgery compared with presurgical averages. The respiration rate increased over time after 24 h postsurgery compared with presurgical values. Although it was clear that the surgery is painful, the drug effects were more difficult to explain. On d 0 and 1, the meloxicam-treated cows ate 3 kg more but spent 101 min/d less time lying on their left side compared with ketoprofen-treated cows. The first stage of a 2-stage fistulation surgery was considered painful based on changes in heart rate, respiration rate, infrared temperature readings, dry matter intake, and time spent lying on the left side. It is clear that left flank surgery is painful and that NSAID can improve outcomes associated with that pain, but we cannot make recommendations as to which NSAID to choose based on these results.