A novel cyclosporin a aqueous formulation for dry eye treatment: in vitro and in vivo evaluation.

PURPOSE: The aim of the present study was the in vitro and in vivo evaluation of a novel aqueous formulation based on polymeric micelles for the topical delivery of cyclosporine A for dry eye treatment. METHODS: In vitro experiments were carried out on primary rabbit corneal cells, which were characterized by immunocytochemistry using fluorescein-labeled lectin I/isolectin B4 for the endothelial cells and mouse monoclonal antibody to cytokeratin 3+12 for the epithelial ones. Living cells were incubated for 1 hour or 24 hours with a fluorescently labeled micelle formulation and analyzed by fluorescence microscopy. In vivo evaluations were done by Schirmer test, osmolarity measurement, CyA kinetics in tears, and CyA ocular distribution after topical instillation. A 0.05% CyA micelle formulation was compared to a marketed emulsion (Restasis). RESULTS: The in vitro experiments showed the internalization of micelles in the living cells. The Schirmer test and osmolarity measurements demonstrated that micelles did not alter the ocular surface properties. The evaluation of the tear fluid gave similar CyA kinetics values: AUC = 2339 ± 1032 min*μg/mL and 2321 ± 881.63; Cmax = 478 ± 111 μg/mL and 451 ± 74; half-life = 36 ± 9 min and 28 ± 9 for the micelle formulation and Restasis, respectively. The ocular distribution investigation revealed that the novel formulation delivered 1540 ± 400 ng CyA/g tissue to the cornea. CONCLUSIONS: The micelle formulation delivered active CyA into the cornea without evident negative influence on the ocular surface properties. This formulation could be applied for immune-related ocular surface diseases.

Viral self-assembly as a thermodynamic process

The protein shells, or capsids, of nearly all spherelike viruses adopt icosahedral symmetry. In the present Letter, we propose a statistical thermodynamic model for viral self-assembly. We find that icosahedral symmetry is not expected for viral capsids constructed from structurally identical protein subunits and that this symmetry requires (at least) two internal switching configurations of the protein. Our results indicate that icosahedral symmetry is not a generic consequence of free energy minimization but requires optimization of internal structural parameters of the capsid proteins

The use of the SeDeM diagram expert system for the formulation of Captopril SR matrix tablets by direct compression

The SeDeM Diagram Expert System has been used to study excipients, Captopril and designed formulations for their galenic characterization and to ascertain the critical points of the formula affecting product quality to obtain suitable formulations of Captopril Direct Compression SR Matrix Tablets. The application of the Sedem Diagram Expert System enables selecting excipients with in order to optimize the formula in the preformulation and formulation studies. The methodology is based on the implementation of ICH Q8, establishing the design space of the formula with the use of experiment design, using the parameters of the SeDeM Diagram Expert System as system responses.

Accounting system for activity standard costs formulation in ERP environment

Toiminnanohjausjärjestelmän implementointi ja sen mukanaan tuomat muutokset tuotekustannuslaskentaan asettavat haasteita yritykselle. Metallitoimialalla toimivassa yrityksessä on havaittu samat haasteet implementoitaessa SAP R/3 toiminnanohjausjärjestelmää ja sen tuotekustannuslaskentatoiminnallisuutta. SAP R/3 tuotekustannuslogiikka tarvitsee tietoa järjestelmän ulkopuolelta, minkä huomioimatta jättäminen vaikuttaa suoraan laskentatarkkuuteen. Diplomityössä kehitetään sekä standardoitu prosessi että laskentajärjestelmä, joiden avulla pystytään laskemaan tarvittavat niin toimintokustannukset eri teräspalvelukeskuksen kuormituspisteille kuin kustannustenvyörytysarvot. Lasketut arvot muodostavat tarvittavat tekijät SAP R/3 tuotekustannuslaskennan master dataan. Tavoitteena on edesauttaa läpinäkyvän kustannustiedon muodostumista. Diplomityö pohjautuu ns. vesiputousmalliin (SDLC). Ensin tunnistetaan reunaehdot ympäristöstä, jossa tuotekustannuslaskenta toteutetaan. Tämä asettaa joustamattomia komponentteja kehitettävälle laskentajärjestelmälle. Joustavat komponentit sen sijaan antavat vapautta laskentajärjestelmälle. Yhdistämällä joustamattomat ja joustavat komponentit saavutetaan järjestelmä, jolla voidaan täydentää SAP R/3 tuotekustannuslaskennan puutteellisuutta.

Modeling of non-isothermalvapor membrane separation with thermodynamic models and generalized mass transfer equations

A rigorous unit operation model is developed for vapor membrane separation. The new model is able to describe temperature, pressure, and concentration dependent permeation as wellreal fluid effects in vapor and gas separation with hydrocarbon selective rubbery polymeric membranes. The permeation through the membrane is described by a separate treatment of sorption and diffusion within the membrane. The chemical engineering thermodynamics is used to describe the equilibrium sorption of vapors and gases in rubbery membranes with equation of state models for polymeric systems. Also a new modification of the UNIFAC model is proposed for this purpose. Various thermodynamic models are extensively compared in order to verify the models' ability to predict and correlate experimental vapor-liquid equilibrium data. The penetrant transport through the selective layer of the membrane is described with the generalized Maxwell-Stefan equations, which are able to account for thebulk flux contribution as well as the diffusive coupling effect. A method is described to compute and correlate binary penetrant¿membrane diffusion coefficients from the experimental permeability coefficients at different temperatures and pressures. A fluid flow model for spiral-wound modules is derived from the conservation equation of mass, momentum, and energy. The conservation equations are presented in a discretized form by using the control volume approach. A combination of the permeation model and the fluid flow model yields the desired rigorous model for vapor membrane separation. The model is implemented into an inhouse process simulator and so vapor membrane separation may be evaluated as an integralpart of a process flowsheet.

Automated formulation of optimisation models for steel beam structures

Over 70% of the total costs of an end product are consequences of decisions that are made during the design process. A search for optimal cross-sections will often have only a marginal effect on the amount of material used if the geometry of a structure is fixed and if the cross-sectional characteristics of its elements are property designed by conventional methods. In recent years, optimalgeometry has become a central area of research in the automated design of structures. It is generally accepted that no single optimisation algorithm is suitable for all engineering design problems. An appropriate algorithm, therefore, mustbe selected individually for each optimisation situation. Modelling is the mosttime consuming phase in the optimisation of steel and metal structures. In thisresearch, the goal was to develop a method and computer program, which reduces the modelling and optimisation time for structural design. The program needed anoptimisation algorithm that is suitable for various engineering design problems. Because Finite Element modelling is commonly used in the design of steel and metal structures, the interaction between a finite element tool and optimisation tool needed a practical solution. The developed method and computer programs were tested with standard optimisation tests and practical design optimisation cases. Three generations of computer programs are developed. The programs combine anoptimisation problem modelling tool and FE-modelling program using three alternate methdos. The modelling and optimisation was demonstrated in the design of a new boom construction and steel structures of flat and ridge roofs. This thesis demonstrates that the most time consuming modelling time is significantly reduced. Modelling errors are reduced and the results are more reliable. A new selection rule for the evolution algorithm, which eliminates the need for constraint weight factors is tested with optimisation cases of the steel structures that include hundreds of constraints. It is seen that the tested algorithm can be used nearly as a black box without parameter settings and penalty factors of the constraints.

Potentiometric titration as a method of determining the stoichiometric dissociation constants of weak acids from the thermodynamic dissociation constants of aqueous solutions at 298.15 K

The simple single-ion activity coefficient equation originating from the Debye-Hückel theory was used to determine the thermodynamic and stoichiometric dissociation constants of weak acids from data concerning galvanic cells. Electromotive force data from galvanic cells without liquid junctions, which was obtained from literature, was studied in conjuction with the potentiometric titration data relating to aqueous solutions at 298.15 K. The dissociation constants of weak acids could be determined by the presented techniques and almost all the experimental data studied could be interpreted within the range of experimental error. Potentiometric titration has been used here and the calculation methods were developed to obtain the thermodynamic and stoichiometric dissociation constants of some weak acids in aqueous solutions at 298.15 K. The ionic strength of titrated solutions were adjusted using an inert electrolyte, namely, sodium or potassium chloride. Salt content alonedetermines the ionic strength. The ionic strength of the solutions studied varied from 0.059 mol kg-1 to 0.37 mol kg-1, and in some cases up to 1.0 mol kg-1. The following substances were investigated using potentiometric titration: aceticacid, propionic acid, L-aspartic acid, L-glutamic acid and bis(2,2-dimethyl-3-oxopropanol) amine.

Dynamic analysis of belt-drives using the absolute nodal coordinate formulation

Belt-drive systems have been and still are the most commonly used power transmission form in various applications of different scale and use. The peculiar features of the dynamics of the belt-drives include highly nonlinear deformation,large rigid body motion, a dynamical contact through a dry friction interface between the belt and pulleys with sticking and slipping zones, cyclic tension of the belt during the operation and creeping of the belt against the pulleys. The life of the belt-drive is critically related on these features, and therefore, amodel which can be used to study the correlations between the initial values and the responses of the belt-drives is a valuable source of information for the development process of the belt-drives. Traditionally, the finite element models of the belt-drives consist of a large number of elements thatmay lead to computational inefficiency. In this research, the beneficial features of the absolute nodal coordinate formulation are utilized in the modeling of the belt-drives in order to fulfill the following requirements for the successful and efficient analysis of the belt-drive systems: the exact modeling of the rigid body inertia during an arbitrary rigid body motion, the consideration of theeffect of the shear deformation, the exact description of the highly nonlinear deformations and a simple and realistic description of the contact. The use of distributed contact forces and high order beam and plate elements based on the absolute nodal coordinate formulation are applied to the modeling of the belt-drives in two- and three-dimensional cases. According to the numerical results, a realistic behavior of the belt-drives can be obtained with a significantly smaller number of elements and degrees of freedom in comparison to the previously published finite element models of belt-drives. The results of theexamples demonstrate the functionality and suitability of the absolute nodal coordinate formulation for the computationally efficient and realistic modeling ofbelt-drives. This study also introduces an approach to avoid the problems related to the use of the continuum mechanics approach in the definition of elastic forces on the absolute nodal coordinate formulation. This approach is applied to a new computationally efficient two-dimensional shear deformable beam element based on the absolute nodal coordinate formulation. The proposed beam element uses a linear displacement field neglecting higher-order terms and a reduced number of nodal coordinates, which leads to fewer degrees of freedom in a finite element.

The potential impact of new effervescent alendronate formulation on compliance and persistence in osteoporosis treatment.

Osteoporotic fractures are a public health problem and their incidence and subsequent economic and social costs are expected to rise in the next future. Different drugs have been developed to reduce osteoporosis and the risk of osteoporotic fractures, and among them, antiresorptive agents, and in particular oral alendronate, are the most widely utilized. However, one of the most common problems with antiresorptive drugs is poor adherence to treatment, which is associated with a high fracture incidence and with an increase in hospitalization costs. One of the main reasons of poor adherence to these treatments is the occurrence of adverse events, mainly at gastrointestinal (GI) level, including dyspepsia, dysphagia, and esophageal ulcers. In light of these considerations the aim of this paper is to perform a literature review to show the pathophysiologic bases of GI alendronate-induced adverse events and how new bisphosphonate formulations like effervescent alendronate can improve compliance and persistence to treatment and decrease the fracture rate incidence in osteoporotic patients.

Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 30-40% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

Development of a PC Tool for Estimating Pressure Drops in Forced-convection Boiler Tubes

Kaksifaasivirtauksen kuvaamiseen käytettävät mallit, ja menetelmät kaksifaasivirtauksen painehäviön määrittämiseksi kehittyvät yhä monimutkaisimmiksi. Höyrystinputkissa tapahtuvien painehäviöiden arvioinnin vaatiman laskennan suorittamiseksi tietokoneohjelman kehittäminen on välttämätöntä. Tässä työssä on kehitetty itsenäinen PC-ohjelma painehäviöiden arvioimiseksi pakotetulle konvektiovirtaukselle pystysuorissa höyrykattilan höyrystinputkissa. Veden ja vesihöyryn aineominaisuuksien laskentaan käytetään IAPWS-IF97 –yhtälökokoelmaa sekä muita tarvittavia IAPWS:n suosittelemia yhtälöitä. Höyrystinputkessa kulloinkin vallitsevan virtausmuodon määrittämiseen käytetään sovelluskelpoisia virtausmuotojen välisiä rajoja kuvaavia yhtälöitä. Ohjelmassa käytetään painehäviön määritykseen kirjallisuudessa julkaistuja yhtälöitä, virtausmuodosta riippuen, alijäähtyneelle virtaukselle, kupla-, tulppa- ja rengasvirtaukselle sekä tulistetun höyryn virtaukselle. Ohjelman laskemia painehäviöarvioita verrattiin kirjallisuudesta valittuihin mittaustuloksiin. Laskettujen painehäviöiden virhe vaihteli välillä –19.5 ja +23.9 %. Virheiden itseisarvojen keskiarvo oli 12.8 %.

Potential of antioxidant extracts produced by aqueous processing ofrenewable resources for the formulation of cosmetics

The performance of natural extracts obtained from underutilized and residual vegetal and macroalgal biomass processed with food-grade green solvents was compared with that of commercial antioxidants. Selected extracts were obtained from two terrestrial sources: winery byproducts concentrate (WBC) and chestnut burs hydrothermally fractionated extract (CBAE), and from two underutilized seaweeds: Sargassum muticum extracts, either extracted with ethanol (SmEE) or after alginate extraction and hydrothermal fractionation (SmAE) and from Ulva lactuca processed by mild acid extraction and membrane concentration (UlAE). These extracts showed in vitro antioxidant properties comparable to commercial antioxidants and were safe for topical use based on the absence of skin-irritant effects at 0.1% on reconstructed human tissues. The stability of several cosmetic model emulsions was assessed during accelerated oxidation assays. The incorporation of natural extracts produced from renewable underutilized resources at 0.4-0.5% in an oil-in-water emulsions reduced lipid oxidation during storage.

Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 30-40% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

Procurement, Quality and Productivity Enhancements and Manufacturing Strategy Formulation Applying Product Life Cycle Method

The objective of the thesis was to create a framework that can be used to define a manufacturing strategy taking advantage of the product life cycle method, which enables PQP enhancements. The starting point was to study synkron implementation of cost leadership and differentiation strategies in different stages of the life cycles. It was soon observed that Porter’s strategies were too generic for the complex and dynamic environment where customer needs deviate market and product specifically. Therefore, the strategy formulation process is based on the Terry Hill’s order-winner and qualifier concepts. The manufacturing strategy formulation is initiated with the definition of order-winning and qualifying criteria. From these criteria there can be shaped product specific proposals for action and production site specific key manufacturing tasks that they need to answer in order to meet customers and markets needs. As a future research it is suggested that the process of capturing order-winners and qualifiers should be developed so that the process would be simple and streamlined at Wallac Oy. In addition, defined strategy process should be integrated to the PerkinElmer’s SGS process. SGS (Strategic Goal Setting) is one of the PerkinElmer’s core management processes. Full Text: Null

Customer expectation study in product development process and its role in strategy formulation

Tämä työ on tehty kansainväliselle metsäteollisuusyritykselle. Työn lähtökohtana oli tarve tutkia yrityksen mahdollisuuksia laajentaa toimintaansa uudelle markkinasegmentille, eläinruokapakkausmarkkinoille. Johtuen maailmanlaajuisesta eläinruoankulutuksen kasvusta, eläinruokapakkaukset ovat yritykselle mielenkiintoinen uusi markkina-alue. Onnistunut markkinoilletulo vaatii asiakastarpeiden ja -odotusten huomioimista tuotekehitys- ja markkinastrategian muodostamisessa. Tämän työn tavoitteena oli selvittää asiakkaiden odotuksia eläinruokapakkauksille, sekä mallintaa alalla vallitsevia ostoprosesseja. Asiakastarvetutkimus suunniteltiin perustuen kirjallisuuteen ja alustaviin markkina- ja asiakasanalyyseihin. Alustavat analyysit ovat tarpeellisia lähtötilanteen ja trendien selvittämiseksi. Itse tutkimus toteutettiin semi-konstruktoituna teemahaastatteluna. Haastateltavat edustivat USA:n ja Euroopan johtavia eläinruokavalmistajia ja pakkausten jatkojalostajia. Työn tuloksena saatiin yksityiskohtaista tietoa asiakkaiden odotuksista eläinruokapakkauksille, paperin ominaisuuksille ja paperitoimittajille. Lisäksi mallinnettiin ostoprosesseja paperitoimittajien, pakkausten jalostajien ja eläinruokavalmistajien välillä. Tulosten perusteella on analysoitu yrityksen mahdollisuuksia menestyä uudella markkinasegmentillä. Lisäksi työssä annettiin ehdotuksia tuotekehitys- ja markkinastrategian muodostamiseen.