Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin

Eye drops of poorly soluble drugs are frequently formulated as suspensions. Bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid, but these factors are still poorly understood. We investigated seven ocular indomethacin suspensions (experimental suspensions with two particle sizes and three viscosities, one commercial suspension) in physical and biological tests. The median particle size (d50) categories of the experimental suspensions were 0.37–1.33 and 3.12–3.50 µm and their viscosity levels were 1.3, 7.0, and 15 mPa·s. Smaller particle size facilitated ocular absorption of indomethacin to the aqueous humor of albino rabbits. In aqueous humor the AUC values of indomethacin suspensions with different particle sizes, but equal viscosity, differed over a 1.5 to 2.3-fold range. Higher viscosity increased ocular absorption 3.4–4.3-fold for the suspensions with similar particle sizes. Overall, the bioavailability range for the suspensions was about 8-fold. Instillation of larger particles resulted in higher tear fluid AUC values of total indomethacin (suspended and dissolved) as compared to application of smaller particles. Despite these tear fluid AUC values of total indomethacin, instillation of the larger particles resulted in smaller AUC levels of indomethacin in the aqueous humor. This suggests that the small particles yielded higher concentrations of dissolved indomethacin in the tear fluid, thereby leading to improved ocular bioavailability. This new conclusion was supported by ocular pharmacokinetic modeling. Both particle size and viscosity have a significant impact on drug concentrations in the tear fluid and ocular drug bioavailability from topical suspensions. Viscosity and particle size are the key players in the complex interplay of drug retention and dissolution in the tear fluid, thereby defining ocular drug absorption and bioequivalence of ocular suspensions

Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin

Eye drops of poorly soluble drugs are frequently formulated as suspensions. Bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid, but these factors are still poorly understood. We investigated seven ocular indomethacin suspensions (experimental suspensions with two particle sizes and three viscosities, one commercial suspension) in physical and biological tests. The median particle size (d50) categories of the experimental suspensions were 0.37–1.33 and 3.12–3.50 µm and their viscosity levels were 1.3, 7.0, and 15 mPa·s. Smaller particle size facilitated ocular absorption of indomethacin to the aqueous humor of albino rabbits. In aqueous humor the AUC values of indomethacin suspensions with different particle sizes, but equal viscosity, differed over a 1.5 to 2.3-fold range. Higher viscosity increased ocular absorption 3.4–4.3-fold for the suspensions with similar particle sizes. Overall, the bioavailability range for the suspensions was about 8-fold. Instillation of larger particles resulted in higher tear fluid AUC values of total indomethacin (suspended and dissolved) as compared to application of smaller particles. Despite these tear fluid AUC values of total indomethacin, instillation of the larger particles resulted in smaller AUC levels of indomethacin in the aqueous humor. This suggests that the small particles yielded higher concentrations of dissolved indomethacin in the tear fluid, thereby leading to improved ocular bioavailability. This new conclusion was supported by ocular pharmacokinetic modeling. Both particle size and viscosity have a significant impact on drug concentrations in the tear fluid and ocular drug bioavailability from topical suspensions. Viscosity and particle size are the key players in the complex interplay of drug retention and dissolution in the tear fluid, thereby defining ocular drug absorption and bioequivalence of ocular suspensions

Development of novel immunization approaches to generate immunity in the female genital tract with special reference to genital herpes

Development of mucosal vaccines for inducing immunity in the female reproductive tract would have profound implications for the prevention of sexually transmitted diseases. Despite numerous efforts, no such vaccines are currently available for human use. The main objective of this doctoral thesis was to develop novel immunization approaches to generate immunity in the female genital tract with special emphasis on immunity against genital herpes. Mammalian innate immune systems sense and respond to pathogens through a series of pattern recognition receptors such as Toll-like receptors (TLRs). Detection of pathogen associated molecular patterns by TLRs triggers a signaling pathway mainly through adaptor protein MyD88, which results in a coordinated set of immune responses that includes both innate and acquired immunity. By using a well-established mouse model of genital HSV-2 infection, it was shown in this thesis that the efficacy of intramuscular immunization with a DNA vaccine encoding glycoprotein D (gD) from HSV-2 can be improved with a timely administration of synthetic oligodeoxynucleotide (ODN) containing immunostimulatory CpG motifs, a TLR9 ligand. Another important finding in this thesis work was introduction of CpG ODN as a potent vaginal adjuvant for induction of acquired immunity in the female genital tract as well as for systemic immune response. Thus, vaginal immunization with HSV-2 gD in combination with CpG ODN induced a potent gD specific antibody as well as cellular immunity, and conferred protection against subsequent vaginal challenge with a lethal dose of HSV-2. The potential of rectal immunization route to induce protective immunity in the female genital tract was also investigated. Thus, rectal immunization with a live attenuated HSV-2 TK- was shown to confer antibody and cellular response as well as protection against an otherwise lethal vaginal challenge with a virulent HSV-2 strain. Importantly, unlike intravaginal route, rectal route was shown to be independent of sex hormonal influence. It was also documented that TLR/MyD88 signaling pathway is important for innate immune protection against primary genital herpes. By contrast, the usage of MyD88 was shown to be dispensable for induction of acquired immune protection induced by vaginal or rectal immunization with HSV-2 TK-. In addition, while rectal immunization with the TLR/MyD88 targeting adjuvant CpG ODN in combination with gD failed to elicit protective immunity, rectal immunization with cholera toxin and gD conferred a potent antibody and cellular immune responses as well as protection against genital herpes. These results have implications for the development of vaccines to generate immunity in the female genital tract against sexually transmitted infections

Tyska språket inom den svenska turismbranschen : En studie av språkbruk i svensk turism

Tyskar reser mest i världen. I Sverige är Tyskland en av de största målmarknaderna. Genom globaliseringen har språk och kommunikation fått en viktig roll i samhället, vilket ökar kravet på kommunikation. Inom turismbranschen används engelska som det främsta kommunikationsspråket. Då inte alla behärskar engelska, kan språk innebära kommunikationsproblem. Med engelskans globala spridning kan det också antas att det bör räcka att kunna tala engelska i många fall. Vår studie har som mål att ge en beskrivning av hur den svenska turismbranschen bemöter tysktalande turister. Syftet med studien är att genom utsagor från intervjuer beskriva hur tysktalande turister bemöts. Det gör vi för att se om det är av relevans att kunna tala tyska inom turismbranschen i Sverige. Med en induktiv ansats och en kvalitativ metod genomfördes intervjuer med representanter från svensk turismbransch, lektorer i tyskundervisning och tyska medborgare. I resultatet av studien framkommer det att turistbyråerna i södra Sverige bemöter tysktalande turister på tyska. Övriga aktörer inom svensk turism gör antagligen inte det i lika stor utsträckning pga. att det finns en brist av tysktalande svenskar på arbetsmarknaden och att aktörerna inte har FörTurs krav på sig att ha tysktalande personal. Vi anser det relevant att turismpersonal kan tala tyska med tysktalande turister, eftersom det visar på gott värdskap mot en målmarknad

Introduktionsutbildning för nyanställda : om individers lärande och socialisationsprocess på SkandiaBanken

Bakgrund: Det blir allt vanligare att företag erbjuder sina nyanställda en introduktionsutbildning för att underlätta vägen i de nya arbetsuppgifterna. Det krävs också av företagen att kontinuerligt utveckla personalens kompetens för att bli konkurrenskraftiga. Då kan en grundlig introduktionsutbildning vara en mycket god investering. Syfte: Syftet med denna uppsats var att analysera den påverkan som ett företags introduktionsutbildning hade på individens lärande, samt betydelsen av socialisationen under denna lärprocess. Metod: Vi valde ett kvalitativt tillvägagångssätt i form av en empirisk studie. Semistrukturerade intervjuer har genomförts med personer som genomgått SkandiaBankens introduktionsutbildning. Därefter bearbetades materialet med hjälp av relevant teori. Resultat: Vi fann att utbildningen ledde till ett i huvudsak anpassningsinriktat lärande. Ett hinder för deltagarnas lärande var att det inte fanns tillräckligt med utrymme för reflektion, och att utbildningen inte är anpassad till de enskilda deltagarnas förkunskaper. Socialisationen i form av metalärande var mycket central i utvecklingen till att bli en del av SkandiaBanken. Nyckelord: Introduktionsutbildning, Introduktion, Personalutbildning, Socialisation, Lärande, Förutsättningar

Rectal immunization generates protective immunity in the female genital tract against herpes simplex virus type 2 infection: relative importance of myeloid differentiation factor 88.

The present study was undertaken to examine the potential of rectal route of immunization for induction of protective immunity in the female genital tract against genital herpes infection in mice. A single rectal immunization of female C57Bl/6 mice with live attenuated herpes simplex virus type 2 lacking thymidine kinase (HSV-2 TK-) was shown to confer HSV-specific cellular and humoral immune responses as well as protection against an otherwise lethal vaginal challenge with a virulent HSV-2 strain. The immunity afforded by rectal immunization with HSV-2 TK- was shown to be independent of sex hormonal influence and the usage of the adaptor protein myeloid differentiation factor 88 (MyD88). Next, the impact of rectal immunization with HSV-2 glycoprotein D (gD) in combination with CpG oligodeoxynucleotide (ODN) or cholera toxin (CT) on induction of immunity against HSV-2 was investigated. Rectal immunization of mice with gD+CpG failed to generate gD specific immune responses and protection against genital herpes infection. Conversely, rectal immunization with gD+CT elicited potent gD-specific cellular immune responses and protection against genital herpes infection through a MyD88-dependent manner. These results highlight the potential of rectal route for the development of novel immunization strategies to elicit immunity in the female genital tract against genital herpes and presumably other sexually transmitted diseases

Antigen-Specific Gene Therapy after Immunisation Reduces the Severity of Collagen-Induced Arthritis

Reestablishment of tolerance induction in rheumatoid arthritis (RA) would be an optimal treatment with few, if any, side effects. However, to develop such a treatment further insights in the immunological mechanisms governing tolerance are needed. We have developed a model of antigen-specific tolerance in collagen type II (CII) induced arthritis (CIA) using lentivirus-based gene therapy. The immunodominant epitope of CII was inserted into a lentivirus vector to achieve expression on the MHC class II molecule and the lentiviral particles were subsequently intravenously injected at different time points during CIA. Injection of lentiviral particles in early phases of CIA, that is, at day 7 or day 26 after CII immunisation, partially prevented development of arthritis, decreased the serum levels of CII-specific IgG antibodies, and enhanced the suppressive function of CII-specific T regulatory cells. When lentiviral particles were injected during manifest arthritis, that is, at day 31 after CII immunisation, the severity of arthritis progression was ameliorated, the levels of CII-specific IgG antibodies decreased and the proportion of T regulatory cells increased. Thus, antigen-specific gene therapy is effective when administered throughout the inflammatory course of arthritis and offers a good model for investigation of the basic mechanisms during tolerance in CIA

Mucin Binding to Moraxella catarrhalis During Airway Inflammation is Dependent on Sialic Acid

Chronic obstructive pulmonary disease (COPD) is associated with colonization by bacterial pathogens and repeated airway infections, leading to exacerbations and impaired lung function. The highly glycosylated mucins in the mucus lining the airways are an important part of the host defense against pathogens. However, mucus accumulation can contribute to COPD pathology. Here, we examined whether inflammation is associated with glycosylation changes that affect interactions between airway mucins and pathogens. We isolated mucins from lower airway samples (LAS, n=4-9) from long-term smokers with and without COPD and from never-smokers. The most abundant terminal glycan moiety was N-acetylneuraminic acid (Neu5Ac) among smokers with and without COPD and N-acetyl-hexoseamine among never-smokers. Moraxella catarrhalis bound to MUC5 mucins from smokers with and without COPD. M. catarrhalis binding correlated with inflammatory parameters and Neu5Ac content. M. catarrhalis binding was abolished by enzymatic removal of Neu5Ac. Furthermore, M. catarrhalis bound to α2-6 sialyl-lactose suggesting that α2-6 sialic acid contributes to M. catarrhalis binding to mucins. Further, we detected more M. catarrhalis binding to mucins from patients with pneumonia than to those from control subjects (n=8-13) and this binding correlated with C-reactive protein and Neu5Ac levels. These results suggest a key role of inflammation induced Neu5Ac in adhesion of M. catarrhalis to airway mucins. Inflammation induced ability of MUC5 mucins to bind M. catarrhalis is likely a host defense mechanism in the healthy lung, although it cannot be excluded that impaired mucociliary clearance limits the effectiveness of this defense in COPD patients