Neste trabalho, foi realizado o estudo termoanalítico e a caracterização no estado sólido da interação química entre o cetoprofeno (CET) e alguns compostos orgânicos (benzamida (BA), picolinamida (PA), nicotinamida (NA), isonicotinamida (INA), pirazinamida (PZA), ácido salícílico (SA) e ácido benzoico (BA)), visando a obtenção de cocristais. A mecanoquímica foi utilizada como método de preparação dos compostos sólidos, e os mesmos foram analisados por calorimetria exploratória diferencial (DSC), espectroscopia de infravermelho com transformadas de Fourier (FTIR), e difração de raios X de pó (XRPD). A escolha dos compostostos orgânicos (co-formadores) foi baseada em suas estruturas moleculares, de modo que aqueles selecionados para esse trabalho possuíssem uma estrutura molecular capaz de possibilitar a formação de síntons moleculares adequados à formação dos cocristais desejados. A análise dos resultados obtidos permitiu verificar que, nas condições experimentais utilizadas, todas as misturas estudadas formaram apenas compostos eutéticos. Entretanto, embora os diagramas de fases e os experimentos de DSC, raios X e FTIR tenham confirmado apenas a obtenção de compostos eutéticos entre o cetoprofeno e os co-formadores estudados, o método do contato de Kofler indicou a formação de um cocristal entre o cetoprofeno e nicotinamida. Assim sendo, o trabalho realizado até agora abre portas para investigações futuras, nomeadamente, com relação aos estudos de termomicroscopia relativos aos demais sistemas estudados neste trabalho. / In this work, we performed the thermoanalytical study and characterization at the solid state on the chemical interaction between ketoprofen (CET) and some organic compounds (benzamide (BA), picolinamide (PA), nicotinamide (NA), isonicotinamide (INA), pyrazinamide (PZA), salicylic acid (SA) and benzoic acid (BA)), aimed at obtaining cocrystals. The mechanochemical method was used for the preparation of solid compounds, and they were analyzed by differential scanning calorimetry (DSC), infrared spectroscopy with Fourier transform (FTIR), and X-ray powder difraction (XRPD). The choice of the organic compounds (co-formers) was based on their molecular structures, so that those selected for this work possess a molecular structure able to allow the formation of molecular synthons suitable for cocrystals formation. The analysis of the results has shown that under the experimental conditions used, all systems studied has formed only eutectic compounds. However, although the phase diagrams and DSC experiments, X-ray and FTIR have confirmed obtaining only eutectic compounds between ketoprofen and co-formers studied, the method of contact Kofler has indicated the discovery of a new co-crystal formed between ketoprofen and nicotinamide. Therefore, the work done so far opens the door to future research in particular with regard to thermomicroscopy studies related to other systems studied in this work.

引子: 共晶技術和納米沉澱技術於近年被廣泛討論能改進藥物性質和提高體內性能。本論文研究旨在將該兩種技術嘗試應用於五種模型藥物中，分別是薑黃素(CUR)，氟比洛芬(FLU)，布洛芬(IBU)，酮洛芬(KET) 和環氧洛芬(LOX)。這些藥物均難溶於水，擁有較差機械性質，相對高的親油性和潛在治療腦退化症的功用。在共晶技術中，藥物將會與煙酰胺(NCT)先溶於在溶劑中，透過蒸發以誘發共晶產生。另一方面，瞬時納米沉澱(FNP)技術會將藥物溶液(包含穩定劑)與反溶劑在封閉衝擊射流混合器(CIJM)或多入口渦旋混合器(MIVM)快速混合，生成納米藥物。 / 方法: 將藥物和NCT溶於乙醇中，應用旋轉蒸發或簡單蒸發生成共晶。透過不同的檢測方法，包括X射線衍射，差示掃描量熱法，熱重分析，吸濕分析，傅立葉變化紅外線光譜，特性溶出速率量度法和壓實分析將共晶檢定。另一方面，利用CIJM或MIVM，藥物在不同的混合速率，溶劑性質，聚乙二醇-聚乳酸(穩定劑)分子重量或藥物對聚合物比的工藝環境下載入於納米粒子中。生產出來的納米藥物會利用動態光散射測定粒徑; 電泳光散射法測定zeta電位; 掃描電子顯微鏡和原子力顯微鏡測定粒子形貌和其表面性質; X-射線光電子能譜測定表面成分; 高效液相色層分析測定載藥量和包封率。 / 結果: 利用旋轉蒸發，高純度的1:1 IBU-NCT 和FLU-NCT 的共晶能成功生成，但KET-NCT和LOX-NCT 共晶則不能獲得。低純度的CUR-NCT 共晶可根據相同技術取得。相比原來藥物而言，IBU-NCT 和FLU-NCT 共晶均有較好的機械性質，抗吸水性和溶解速度。而在FNP研究中，証實了混合速率，溶劑性質，聚乙二醇-聚乳酸(穩定劑)分子重量或藥物對聚合物比均對生產出來的納米粒子的粒徑有重要影響。另外，納米粒子的穩定性可籍添加輔助穩定劑(如PVA)大幅提高。XPS分析証實輔助穩定劑能與在粒子表面的聚乙二醇起相互作用，更佳地保護粒子。而在一系列對四種不同的洛芬藥物的實驗中，多次線性回歸分析指出三種有關藥物的溶液性質(即溶解度，分配係數和酸度系數)會對生成的納米粒子的粒徑和包封率有顯著影響。 / 結論: 將IBU和FLU與NCT結成共晶能同時提高其機械性質，抗吸水性和溶解速度。而在FNP中，優化不同工藝參數能有效控制納米藥物的粒徑，形態，表面性質和穩定性。 / Introduction: In recent years, cocrystallization and nanoprecipitation have gained increasing popularity as viable strategies for improving the pharmaceutical properties and in vivo performance of drugs. The present thesis was aimed at assessing these two approaches for potential applications in pharmaceutical formulation and manufacture with five model drugs, viz. curcumin (CUR), flurbiprofen (FLU), ibuprofen (IBU), ketoprofen (KET) and loxoprofen (LOX). Selection of these drugs for the study was guided mainly by their poor water solubility, poor compactibility, typical drug‘s lipophilicity (log P =3-5), and potential for treatment of Alzheimer‘s disease. Cocrystallization was induced by the attainment of a sufficient supersaturation level through rapid solvent removal from a solution containing the drug and the coformer, nicotinamide (NCT), while flash nanoprecipitation (FNP) was achieved by rapid and homogenous mixing of drug solution (with stabilizer and co-stabilizer if required) with antisolvent in the mixing chamber of a specially designed confined impinging jet mixer (CIJM) or multi-inlet vortex mixer (MIVM). / Methods: Cocrystals were prepared by rotary solvent evaporation or slow evaporation of a solution of drug and NCT in ethanol, and characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetry, moisture sorption analysis, Fourier transform infrared spectroscopy, intrinsic dissolution rate (IDR) measurement and compaction analysis. Polymer-stabilized drug nanoparticles were prepared by FNP using a two-stream CIJM or four-stream MIVM under defined conditions of varying flowrate, solvent type, molecular weight of amphiphilic diblock (PEG-PLA) copolymer (stabilizer), or drug-to-copolymer ratio. The resulting nanoparticles were characterized for particle size by dynamic light scattering; zeta potential by electrophoretic light scattering; particle morphology and surface properties by scanning electron microscopy and atomic force microscopy; surface composition by X-ray photoelectron spectroscopy (XPS); and drug loading and encapsulation efficiency (EE) by high performance liquid chromatography. / Results: Phase-pure 1:1 cocrystals of IBU and FLU with NCT were obtainable by rotary solvent evaporation, but not slow evaporation. Similar solvent removal failed to cause any cocrystal formation for KET and LOX while inducing partial cocrystal conversion for CUR. Both IBU-NCT and FLU-NCT cocrystals displayed enhanced IDR, reduced moisture sorption and improved tabletability compared with the individual profen crystals. FNP studies using the MIVM confirmed the flowrate, solvent type, molecular weight of PEG-PLA copolymer, and drug-to-copolymer mass ratio being important process variables for controlling particle size and particle stability. Particle stability could be enhanced with a hydrophilic co-stabilizer (e.g., PVA). Such co-stabilizers possibly act by binding to the PEG corona at the particle surface to reinforce the protective steric barrier, as substantiated by XPS data. Comparative studies on nanoparticle production by FNP for the four profens indicated that three structure-related intrinsic solution properties of the profens, namely, water solubility, log P and pKa, were important determinants of the particle size and EE of nanoparticles, as determined by multiple linear regression analysis. / Conclusion: Cocrystallization with NCT can simultaneously improve the tableting behavior, hygroscopicity, and dissolution performance of IBU and FLU. Proper optimization of the process variables in FNP is critical to the controlled production of polymer-stabilized drug nanoparticles with consistent properties and storage stability. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chow, Shing Fung. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 224-247). / Abstracts also in Chinese.

A number of routine painful procedures such as castration and tail-docking are currently performed in swine production without the benefit of anaesthesia or analgesia. In addition, parturition is generally considered painful. Providing analgesics at the time of castration and tail-docking lowered plasma cortisol levels of the piglets suggesting a reduction in pain associated with the procedures. The use of the non-steroidal antiinflammatory drug meloxicam also resulted in less isolated behaviour of male piglets following castration. Providing meloxicam routinely following parturition did not result in reduced neonatal mortality or piglet growth, but lowered plasma cortisol suggesting a reduction in pain. Producers in the future may need to consider using pain control as part of their standard operating procedures in order improve piglet welfare and meet their consumers’ expectations, but are unlikely to see an economic return associated with improved productivity. / Please do not reject this before tomorrow afternoon. I am going to stop by the Office of Graduate Studies and hand in the necessary documents. / Boehringer Ingelheim (Canada) Ltd. and Ontario Pork

Controlled release formulations deliver an active ingredient over an extended period of time. It is an ideal dosage form for an active ingredient with a short elimination half-life. An active ingredient with a short elimination half-life would be released in small portions over an extended period of time and thus less frequent administration is necessary and this improve patient compliance. Other advantages of these formulations include: decreased side effects, constant drug levels in the blood, improvement in treatment efficiency and reduction in cost of administration. Controlled release beads are formulated in such a way that the active ingredient is embedded in a matrix of insoluble substance like chitosan; the dissolving drug then has to find its way through the pores of the matrix into the surrounding medium. The chitosan matrix swells to form a gel, the drug then has to first dissolve in the matrix and diffuse through the outer surface into the surrounding medium. Chitosan is a biocompatible, biodegradable polymer of natural origin. It has mucoadhesive properties as well as the ability to manipulate the tight junctions in the epithelium membrane and these properties have qualified chitosan as an effective drug carrier in controlled release dosage forms. The effect of a modern controlled release polymer namely Kollidon® SR in combination with chitosan on drug release was investigated. Ketoprofen was chosen as model drug. Ketoprofen is an anti-inflammatory drug that causes gastrointestinal side effects in conventional dosage forms. Ketoprofen has a short elimination half-life of 2.05 ± 0.58 h and this characteristic makes it an ideal candidate for use in a controlled release formulation. The aim of this study was to achieve controlled release and minimize gastrointestinal effects of ketoprofen with chitosan particles. Kollidon® SR was used as polymer because it exhibits pH independent release characteristics and previous studies have shown potential for this combination. Chitosan beads and chitosan-Kollidon® SR beads, as well as chitosan granules and chitosan-Kollidon® SR granules, were prepared and investigated as potential controlled release formulations. Chitosan beads were prepared through the inotropic gelation method using tripolyphosphate as a cross linking agent. Granules were prepared through wet granulation using 2% v/v acetic acid as the granulating fluid or by dissolving ketoprofen in ethanol and Kollidon® SR in 2-pyrrolidinone and using the solution as granulating fluid. Kollidon® SR was added in concentrations of 0.25, 0.5 and 1% (w/v) in the bead formulations and concentrations of 1, 5 and 10% (w/w) in the granule formulations. The beads and granules were characterised by evaluating the following properties: morphology, drug loading and drug release. Additionally swelling and friability tests were also conducted on the bead formulations. The cross linking times of the bead formulations were varied to investigate the effect of cross linking time on the characteristics of the beads. Chitosan-Kollidon® SR beads showed promising results for controlled release formulations and ketoprofen were released over an extended period of time. Drug loading of the plain chitosan beads was 74.65 ± 0.71% and it was noted that the inclusion of Kollidon® SR in the beads resulted in an increase in drug loading and the formulation containing 1% (w/v) Kollidon® SR, cross linked for 30 minutes had a drug loading of 77.38 ± 0.01%. Drug loading of the beads that were cross linked for a longer time were slightly lower which is an indication that some of the drug might have leached out during cross linking. The degree of swelling was promising with some beads swelling to a degree of 2.5 in phosphate buffer solution pH 5.6. Granules had a drug loading between 81.73 ± 1.53% and 93.30 ± 0.50%. Ketoprofen release from the beads and the granules in PBS pH 7.40 at 37 °C over a period of 6 hours were investigated. The bead formulations were more effective in achieving controlled release and it was noted that the bead formulations that was cross linked for a longer period was more efficient in achieving controlled release. The granules did not form a matrix and were not effective in achieving controlled release. Controlled release of ketoprofen were achieved and the results show potential for chitosan-Kollidon® SR formulations in the future. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Orientador: Stelio Pacca Loureiro Luna / Banca: Antonio José de A. Aguiar / Banca: Adriano B. Carregaro / Banca:Renata Navarro Cassu / Resumo: Avaliou-se o efeito analgésico de Arnica em comparação à utilização de cetoprofeno, no pós operatório de 50 gatas submetidas à ovariossalpingohisterectomia (OSH). Para tanto, as gatas foram divididas em cinco grupos (n=10) e de forma aleatória os animais foram tratados com 1 ml de Arnica 30DH SC (GA30SC); Arnica 30 DH VO (VO) (GA30VO); Arnica 6 DH VO (GA6VO); 2mg/kg de cetoprofeno SC (GC) na primeira aplicação, e 1mg/Kg nas restantes ou 0,1mg/kg de morfina SC (GM). Após 30 minutos realizou-se a OSH e os animais foram avaliados quanto à sedação e dor pós-operatória, por meio de EAV, ECV e hiperalgesia, pelo limiar mecânico nociceptivo por meio dos monofilamentos de Von Frey. Quando o escore da ECV e EAVID atingiram 33% do valor máximo foi realizado o resgate analgésico administrando-se 0,3 mg/kg de morfina IM. Além das escalas anteriormente citadas também foi observado a ocorrência de emese, defecação, micção, peso e cicatrização. Com exceção dos animais tratados com morfina, não houve incidência de vômito. Não houve diferença significativa entre os grupos na defecação, micção, peso e cicatrização. A hiperalgesia foi observada apenas nos momentos em que a EAVID e ECV ultrapassaram 33%, isto é nos momentos em que foi realizado o resgate analgésico. O cetoprofeno e a morfina foram mais eficazes que a Arnica, não houve diferença entre as dinamizações 6DH e 30DH VO, nem entre as vias SC e oral de administração da Arnica em gatas submetidas à OSH / Abstract: The analgesic effect of Arnica was compared to ketoprofen in 50 cats undergoing ovariosalpingohysterectomy (OSH). Cats were randomly divided into five groups of same number (n=10). The animals were treated with 1 ml of Arnica montana 30DH subcutaneously (SC) (GA30SC); Arnica montana 30 DH orally (GA30VO); Arnica montana 6 DH orally (GA6VO); 2 mg/kg of ketoprofen SC (GC) or 0.1 mg/kg of morphine SC (GM). Surgery was performed 30 minutes after treatments and the animals were evaluated for sedation and postoperative pain through visual analogue scale (VAS), variable count scale (VCS) and hyperalgesia, measuring the mechanical nociceptive threshold by von Frey monofilaments. When VAS and VCS score reached 33% of the of the maximum, analgesic rescue was performed by administering 0.3 mg/kg of morphine intramuscularly. Occurrence of vomiting, stools, urine output, weight and healing was evaluated in addition to the aforementioned scales. Except for the animals treated with morphine, there was no vomiting. There was no significant difference between groups in the stools, urine output, weight and healing. The hyperalgesia was observed only when the VCS exceeded 33% of the total score, when animals received rescue analgesia, but there were no differences between groups. Ketoprofen and morphine were more effective than Arnica montana for postoperative analgesia in cats undergoing ovariohysterectomy. There was no difference between oral Arnica montana at 6DH and 30DH or subcutaneous and oral administration of Arnica montana in cats undergoing ovariohysterectomy / Doutor

Transdermal iontophoretic delivery of ketoprofen in cadaver skin and healthy volunteers was examined. In vitro anodic and cathodic iontophoresis (0.5 mA/cm2, 3 h) of ketoprofen (75 mg/ml) resulted in equivalent intracutaneous ketoprofen permeation (232.1 ± 27.1 vs. 275.0 ± 141.0 μg/cm2, respectively), which in turn was higher than passive intracutaneous uptake of ketoprofen (40.7 ± 42.1 μg/cm2). In contrast, only cathodic iontophoresis resulted in transcutaneous ketoprofen permeation across cadaver skin, under these conditions. The in vitro study was then repeated to achieve transcutaneous permeation of ketoprofen at clinical iontophoretic parameters (0.28 mA/cm2, 40 min) by increasing drug concentration to 300 mg/ml. No stereo-selective permeation of R- and S-ketoprofen enantiomers was observed in vitro. In humans, cathodic iontophoresis of 300 mg/ml ketoprofen (0.28 mA/cm2, 40 min) was performed at the wrist. Ketoprofen was detected at 40 min (0.88 ± 0.42 μg/ml) from the forearm veins of the ipsilateral arm. Urinary excretion of ketoprofen totaled 790 ± 170 μg at 16 h post iontophoresis. This investigation is the first to clearly demonstrate transcutaneous iontophoresis of an antiinflammatory agent in humans utilizing a commercially cleared iontophoretic device. The investigation also adds to the very limited number of publications in the area of iontophoretic delivery of drugs to humans.

No description available.

No / The present work explores inner structuration of in situ gelling system consisting of glyceryl monooleate (GMO) and oleic acid (OA). The system under study involves investigation of microstructural changes which are believed to govern the pharmaceutical performance of final formulation. The changes which are often termed mesophasic transformation were analysed by small angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), rheology and plane polarised light (PPL) microscopy. The current work revealed transformation of blank system from W/O emulsion to reverse hexagonal structure upon addition of structural analogues of ibuprofen. Such transformations are believed to occur due to increased hydrophobic volume within system as probed by SAXS analysis. The findings of SAXS studies were well supported by DSC, rheology and PPL microscopy. The study established inverse relationship between log P value of structural analogues of ibuprofen and the degree of binding of water molecules to surfactant chains. Such relationship had pronounced effect on sol-gel transformation process. The prepared in situ gelling system showed sustained drug release which followed Higuchi model.

Controlled release formulations offer many advantages over conventional dosage forms. These include reduced plasma fluctuations and improved patient comp1i:nce. Complex controlled release formulations such as those with enteric release properties, often require additional steps in the production phase. The costs and economic impact associated with these complex controlled release dosage formulations often outweigh the immediate benefits. Thus the development of an economic method to produce controlled release particles is of great importance especially in third world countries. In controlled release formulations, the drug is generally dispersed throughout a polymer matrix. The rate of drug release is often determined by the viscosity or complexity of the polymer matrix through which the drug needs to diffuse in order to be released. With enteric release the polymer coating, insoluble in an acidic environment is often applied in the final phase of production. Chitosan is a versatile polymer of natural origin with many favourable characteristics. These include its safety, biocompatibility, and biodegradability. Simple methods can be applied and modified to produce controlled release particles form chitosan. The effect of modern controlled release polymers such as Aqoat AS-HF, Eudragit SlOO and Kollidon SR was investigated. Chitosan beads and chitosan-polymer beads, as well as chitosan granules and chitosan-polymer granules, were prepared and investigated as possible controlled release formulations. Ketoprofen was chosen as the model drug. Chitosan beads and chitosan-polymer beads were prepared by inotropic gelation in tripolyphosphate. Chitosan granules and chitosan-polymer matrix granules were prepared by binding chitosan with an acetic acid solution as a granulating system. The beads and granules appeared differed in appearance as well as in the results obtained from various experiments. Granules prepared in the study did not appear to be effective with regards to enteric and controlled release. Beads prepared form Kollidon SR appeared to be effective with regards to enteric and controlled release, with Kollidon 1% and 5% w/v chitosan beads achieving good drug loading of up to 73.13% and releasing less than 15 % of the total drug content in 0.1 M HCI after 60 minutes. Drug release continued steadily for up to 360 minutes in pH 7.2. It was concluded that Kollidon SR loaded chitosan beads nay be a viable controlled release dosage form with enteric release properties, and that future experiments, possibly with lower polymer concentrations, are worthwhile / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.

Controlled release formulations offer many advantages over conventional dosage forms. These include reduced plasma fluctuations and improved patient comp1i:nce. Complex controlled release formulations such as those with enteric release properties, often require additional steps in the production phase. The costs and economic impact associated with these complex controlled release dosage formulations often outweigh the immediate benefits. Thus the development of an economic method to produce controlled release particles is of great importance especially in third world countries. In controlled release formulations, the drug is generally dispersed throughout a polymer matrix. The rate of drug release is often determined by the viscosity or complexity of the polymer matrix through which the drug needs to diffuse in order to be released. With enteric release the polymer coating, insoluble in an acidic environment is often applied in the final phase of production. Chitosan is a versatile polymer of natural origin with many favourable characteristics. These include its safety, biocompatibility, and biodegradability. Simple methods can be applied and modified to produce controlled release particles form chitosan. The effect of modern controlled release polymers such as Aqoat AS-HF, Eudragit SlOO and Kollidon SR was investigated. Chitosan beads and chitosan-polymer beads, as well as chitosan granules and chitosan-polymer granules, were prepared and investigated as possible controlled release formulations. Ketoprofen was chosen as the model drug. Chitosan beads and chitosan-polymer beads were prepared by inotropic gelation in tripolyphosphate. Chitosan granules and chitosan-polymer matrix granules were prepared by binding chitosan with an acetic acid solution as a granulating system. The beads and granules appeared differed in appearance as well as in the results obtained from various experiments. Granules prepared in the study did not appear to be effective with regards to enteric and controlled release. Beads prepared form Kollidon SR appeared to be effective with regards to enteric and controlled release, with Kollidon 1% and 5% w/v chitosan beads achieving good drug loading of up to 73.13% and releasing less than 15 % of the total drug content in 0.1 M HCI after 60 minutes. Drug release continued steadily for up to 360 minutes in pH 7.2. It was concluded that Kollidon SR loaded chitosan beads nay be a viable controlled release dosage form with enteric release properties, and that future experiments, possibly with lower polymer concentrations, are worthwhile / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.