Browsing by Subject "DELIVERY"

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  • Germini, Giorgia; Peltonen, Leena (2021)
    The aim of the study was to prepare indomethacin nanocrystal-loaded, 3D-printed, fast-dissolving oral polymeric film formulations. Nanocrystals were produced by the wet pearl milling technique, and 3D printing was performed by the semi-solid extrusion method. Hydroxypropyl methyl cellulose (HPMC) was the film-forming polymer, and glycerol the plasticizer. In-depth physicochemical characterization was made, including solid-state determination, particle size and size deviation analysis, film appearance evaluation, determination of weight variation, thickness, folding endurance, drug content uniformity, and disintegration time, and drug release testing. In drug nanocrystal studies, three different stabilizers were tested. Poloxamer F68 produced the smallest and most homogeneous particles, with particle size values of 230 nm and PI values below 0.20, and was selected as a stabilizer for the drug-loaded film studies. In printing studies, the polymer concentration was first optimized with drug-free formulations. The best mechanical film properties were achieved for the films with HPMC concentrations of 2.85% (w/w) and 3.5% (w/w), and these two HPMC levels were selected for further drug-loaded film studies. Besides, in the drug-loaded film printing studies, three different drug levels were tested. With the optimum concentration, films were flexible and homogeneous, disintegrated in 1 to 2.5 min, and released the drug in 2-3 min. Drug nanocrystals remained in the nano size range in the polymer films, particle sizes being in all film formulations from 300 to 500 nm. When the 3D-printed polymer films were compared to traditional film-casted polymer films, the physicochemical behavior and pharmaceutical performance of the films were very similar. As a conclusion, 3D printing of drug nanocrystals in oral polymeric film formulations is a very promising option for the production of immediate-release improved- solubility formulations.
  • Toijonen, Anna E.; Heinonen, Seppo T.; Gissler, Mika V. M.; Macharey, Georg (2020)
    Purpose To determine if the common risks for breech presentation at term labor are also eligible in preterm labor. Methods A Finnish cross-sectional study included 737,788 singleton births (24-42 gestational weeks) during 2004-2014. A multivariable logistic regression analysis was used to calculate the risks of breech presentation. Results The incidence of breech presentation at delivery decreased from 23.5% in pregnancy weeks 24-27 to 2.5% in term pregnancies. In gestational weeks 24-27, preterm premature rupture of membranes was associated with breech presentation. In 28-31 gestational weeks, breech presentation was associated with maternal pre-eclampsia/hypertension, preterm premature rupture of membranes, and fetal birth weight below the tenth percentile. In gestational weeks 32-36, the risks were advanced maternal age, nulliparity, previous cesarean section, preterm premature rupture of membranes, oligohydramnios, birth weight below the tenth percentile, female sex, and congenital anomaly. In term pregnancies, breech presentation was associated with advanced maternal age, nulliparity, maternal hypothyroidism, pre-gestational diabetes, placenta praevia, premature rupture of membranes, oligohydramnios, congenital anomaly, female sex, and birth weight below the tenth percentile. Conclusion Breech presentation in preterm labor is associated with obstetric risk factors compared to cephalic presentation. These risks decrease linearly with the gestational age. In moderate to late preterm delivery, breech presentation is a high-risk state and some obstetric risk factors are yet visible in early preterm delivery. Breech presentation in extremely preterm deliveries has, with the exception of preterm premature rupture of membranes, similar clinical risk profiles as in cephalic presentation.
  • Poller, Bettina; Strachan, Clare; Broadbent, Roland; Walker, Greg F. (2017)
    The purpose of this study was to evaluate electrospun drug loaded nanofibers as a new matrix for mini tablets. Prednisone, a poorly water-soluble drug, was loaded into povidone (polyvinylpyrrolidone, PVP) nanofibers using the process of electrospinning. The drug-loaded nanofiber mat was compressed into minitablets with a 2 mm diameter and a height of 2.63 0.04 mm. SEM analysis of the minitablet identified a nano-web structure with a nanofiber diameter in the range of 400-500 nm. The minitablets met the requirements of the US Pharmacopeia with respect to content uniformity and friability. DSC and XRPD analysis of the minitablet indicated that the drug-polymer mixture was a one-phase amorphous system. XRPD analysis of the drug loaded nanofiber mat after 10-months of storage at ambient temperature showed no evidence of recrystallization of the drug. Solubility and dissolution properties of the drug formulated into a nanofiber mat and minitablet were evaluated. These results show that electrospun nanofibers may provide a useful matrix for the further development of minitablets. (C) 2017 Elsevier B.V. All rights reserved.
  • Nahm, Daniel; Weigl, Franziska; Schaefer, Natascha; Sancho, Ana; Frank, Andreas; Groll, Jürgen; Villmann, Carmen; Schmidt, Hans-Werner; Dalton, Paul D.; Luxenhofer, Robert (2020)
    In this study, we designed a novel biomaterial ink platform based on hydrophilic poly(2-ethyl-2-oxazine) (PEtOzi) specifically for melt electrowriting (MEW). This material crosslinks spontaneously after processing via dynamic Diels–Alder click chemistry. These direct-written microperiodic structures rapidly swell in water to yield thermoreversible hydrogels. These hydrogels are robust enough for repeated aspiration and ejection through a cannula without structural damage, despite their high water content of 84%. Moreover, the scaffolds retain functional groups for modification using click chemistry and therefore can be readily functionalized as demonstrated using fluorophores and peptides to facilitate visualization and cell attachment. The PEtOzi hydrogel developed here is compatible with confocal imaging and staining protocols for cells. In summary, an advanced material platform based on PEtOzi is reported that is compatible with MEW and results in functionalizable chemically crosslinked microperiodic hydrogels.
  • Sakari Lintinen, Kalle; Luiro, Sanna; Figueiredo, Patricia; Sakarinen, Ekaterina; Mousavi, Zekra; Seitsonen, Jani; N. S. Rivière, Guillaume; Mattinen, Ulriika; Niemelä, Matti; Tammela, Päivi; Österberg, Monika; Johansson, Leena-Sisko; Bobacka, Johan; Santos, Hélder A.; A. Kostiainen, Mauri (2019)
    Acid-precipitated lignin nanoparticles with a cationic polymer coating exhibit antibacterial activity when infused with silver. While the use of such particles would be beneficial due to their high antibacterial activity with a low silver content, their production holds steps that are difficult to scale up to inexpensive industrial manufacture. For example, the production of acid-precipitated lignin nanoparticles requires the use of ethylene glycol, which is not easily recycled. Furthermore, the binding of silver to these particles is weak, and thus the particles need to be used rapidly after preparation. Here, we show that with a deprotonation reaction of an organic solution of anhydrous lignin and subsequent ion exchange with silver nitrate and colloid formation by solvent exchange, highly spherical silver carboxylate colloidal lignin particles (AgCLPs) can be prepared. Silver is not released from the particles in deionized water but can be released in physiological conditions, shown by their high antibacterial efficacy with low silver loading. In comparison to lignin nanoparticles with weakly bound silver, AgCLPs have high antibacterial activity even without cationic polyelectrolyte coating, and they retain their antibacterial activity for days. While the rapid depletion of silver from silver-infused lignin nanoparticles can be considered beneficial for some applications, the sustained antibacterial activity of the AgCLPs with ionically bound silver will enable their use in applications where silver nanoparticles have been previously used. Our results demonstrate that CLPs, which can be produced with a closed cycle process on a large scale, can be rapidly and quantitatively functionalized into active materials.
  • Ahmadian, Zainab; Rebelo Correia, Alexandra Maria; Hasany, Masoud; Figueiredo, Patricia; Dobakhti, Faramarz; Reza Eskandari, Mohammad; Hosseini, Seyed; Abiri, Ramin; Khorshid, Shiva; Hirvonen, Jouni; Santos, Hélder A.; Shahbazi, Mohammad-Ali (2021)
    Extracellular matrix‐mimicking hydrogels with antioxidant, hemostasis, and antibacterial properties offer translating avenues towards wound repair through the promotion of fibroblast proliferation. In article number 2001122 by Hélder A. Santos, Mohammad‐Ali Shahbazi, and co‐workers, hydrogen bonding among the functional groups of gelatin and tannic acid creates a biocompatible hydrogel, where the improvement of re‐epithelialization and collagen deposition are its main features to treat full‐thickness wounds.
  • Uudekll, Peep; Kozlova, Jekaterina; Mandar, Hugo; Link, Joosep; Sihtmae, Mariliis; Kaosaar, Sandra; Blinova, Irina; Kasemets, Kaja; Kahru, Anne; Stern, Raivo; Tatte, Tanel; Kukli, Kaupo; Tamm, Aile (2017)
    Spherical nickel particles with size in the range of 100-400 nm were synthesized by non-aqueous liquid phase benzyl alcohol method. Being developed for magnetically guided biomedical applications, the particles were coated by conformal and antimicrobial thin titanium oxide films by atomic layer deposition. The particles retained their size and crystal structure after the deposition of oxide films. The sensitivity of the coated particles to external magnetic fields was increased compared to that of the uncoated powder. Preliminary toxicological investigations on microbial cells and small aquatic crustaceans revealed non-toxic nature of the synthesized particles.
  • Rautamo, Maria M; Kvarnström, Kirsi; Siven, Mia; Airaksinen, Marja; Lahdenne, Pekka Olavi; Sandler, Niklas (2020)
    The utilization of three-dimensional (3D) printing technologies as innovative manufacturing methods for drug products has recently gained growing interest. From a technological viewpoint, proof-of-concept on the performance of different printing methods already exist, followed by visions about future applications in hospital or community pharmacies. The main objective of this study was to investigate the perceptions of healthcare professionals in a tertiary university hospital about oral 3D-printed medicines for pediatric patients by means of focus group discussions. In general, the healthcare professionals considered many positive aspects and opportunities in 3D printing of pharmaceuticals. A precise dose as well as personalized doses and dosage forms were some of the advantages mentioned by the participants. Especially in cases of polypharmacy, incorporating several drug substances into one product to produce a polypill, personalized regarding both the combination of drug substances and the doses, would benefit drug treatments of several medical conditions and would improve adherence to medications. In addition to the positive aspects, concerns and prerequisites for the adoption of 3D printing technologies at hospital settings were also expressed. These perspectives are suggested by the authors to be focus points for future research on personalized 3D-printed drug products.
  • Rimpelä, Anna-Kaisa; Reunanen, Saku; Hagström, Marja; Kidron, Heidi; Urtti, Arto (2018)
    Pharmacokinetics in the posterior eye segment has therapeutic implications due to the importance of retinal diseases in ophthalmology. In principle, drug binding to the components of the vitreous, such as proteins, collagen, or glycosaminoglycans, could prolong ocular drug retention and modify levels of pharmacologically active free drug in the posterior eye segment. Since drug binding in the vitreous has been investigated only sparsely, we studied vitreal drug binding of 35 clinical small molecule drugs. Isolated homogenized porcine vitreous and the drugs were placed in a two compartment dialysis system that was used to separate the bound and unbound drug. Free drug concentrations and binding percentages were quantitated using LC-MS/MS. Drug binding levels varied between 21 and 74% in the fresh vitreous and 0 and 64% in the frozen vitreous. The vitreal binding percentages did not correlate with those in plasma. Our data-based pharmacokinetic simulations suggest that vitreal binding of small molecule drugs has only a modest influence on the AUC of free drug or drug half-life in the vitreous. Therefore, it is likely that vitreal binding is not a major reason for interindividual variability in ocular drug responses or drug-drug interactions.
  • Fontana, Flavia; Fusciello, Manlio; Groeneveldt, Christianne; Capasso, Cristian; Chiaro, Jacopo; Feola, Sara; Liu, Zehua; Mäkilä, Ermei; Salonen, Jarno; Hirvonen, Jouni; Cerullo, Vincenzo; Santos, Hélder A. (2019)
    Recent approaches in the treatment of cancer focus on involving the immune system to control the tumor growth. The administration of immunotherapies, like checkpoint inhibitors, has shown impressive results in the long term survival of patients. Cancer vaccines are being investigated as further tools to prime tumor-specific immunity. Biomaterials show potential as adjuvants in the formulation of vaccines, and biomimetic elements derived from the membrane of tumor cells may widen the range of antigens contained in the vaccine. Here, we show how mice presenting an aggressive melanoma tumor model treated twice with the complete nanovaccine formulation showed control on the tumor progression, while in a less aggressive model, the animals showed remission and control on the tumor progression, with a modification in the immunological profile of the tumor microenvironment. We also prove that co-administration of the nanovaccine together with a checkpoint inhibitor increases the efficacy of the treatment (87.5% of the animals responding, with 2 remissions) compared to the checkpoint inhibitor alone in the B16.OVA model. Our platform thereby shows potential applications as a cancer nanovaccine in combination with the standard clinical care treatment for melanoma cancers.
  • Macharey, Georg; Gissler, Mika; Rahkonen, Leena; Ulander, Veli-Matti; Vaisanen-Tommiska, Mervi; Nuutila, Mika; Heinonen, Seppo (2017)
    Purpose The aim of this study was to estimate whether breech presentation at term was associated with known individual obstetric risk factors for adverse fetal outcome. Methods This was a retrospective, nationwide Finnish population-based cohort study. Obstetric risks in all breech and vertex singleton deliveries at term were compared between the years 2005 and 2014. A multivariable logistic regression model was used to determine significant risk factors. Results The breech presentation rate at term for singleton pregnancies was 2.4%. The stillbirth rate in term breech presentation was significantly higher compared to cephalic presentation (0.2 vs 0.1%). The odds ratios (95% CIs) for fetal growth restriction, oligohydramnios, gestational diabetes, a history of cesarean section and congenital fetal abnormalities were 1.19 CI (1.07-1.32), 1.42 CI (1.27-1.57), 1.06 CI (1.00-1.13), 2.13 (1.98-2.29) and 2.01 CI (1.92-2.11). Conclusions The study showed that breech presentation at term on its own was significantly associated with antenatal stillbirth and a number of individual obstetric risk factors for adverse perinatal outcomes. The risk factors included oligohydramnios, fetal growth restriction, gestational diabetes, history of caesarean section and congenital anomalies.
  • Jacob, Louis; Weber, Katherina; Sechet, Ingeborg; Macharey, Georg; Kostev, Karel; Ziller, Volker (2016)
    To analyze the impact of caesarean section (CS) on fertility and time to pregnancy in German gynecological practices. Women initially diagnosed for the first time with a vaginal delivery (VD) or CS between 2000 and 2013 were identified by 227 gynecologists in the IMS Disease Analyzer database. They were included if they were aged between 16 and 40 years, and were not previously diagnosed with female sterility. The two main outcomes were the first-time diagnosis of female sterility and the time between the first delivery and the next pregnancy within 10 years. A multivariate Cox regression model was used to predict these outcomes on the basis of patient characteristics. 6483 patients were included in the CS group and 6483 in the VD group. Mean age was 30.6 years and the proportion of individuals with private health insurance amounted to 9.0 %. Within 10 years of the index date, 19.5 % of women who delivered by CS and 18.3 % of women who delivered vaginally were diagnosed with sterility (p value = 0.0148). CS and polycystic ovary syndrome significantly increased the risk of sterility. Within 10 years of the index date, 57.9 % of women who underwent a CS and 64.0 % of women who delivered vaginally were pregnant for the second time (p value <0.001). CS, polycystic ovary syndrome, and the deterioration of menstrual cycle significantly decreased the chance of becoming pregnant a second time. CS is associated with an increased risk of sterility and a decreased number of subsequent pregnancies in Germany.
  • Barok, Mark; Puhka, Maija; Vereb, Gyorgy; Szollosi, Janos; Isola, Jorma; Joensuu, Heikki (2018)
    Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that carries a cytotoxic drug (DM1) to HER2-positive cancer. The target of T-DM1 (HER2) is present also on cancer-derived exosomes. We hypothesized that exosome-bound T-DM1 may contribute to the activity of T-DM1. Methods: Exosomes were isolated from the cell culture medium of HER2-positive SKBR-3 and EFM-192A breast cancer cells, HER2-positive SNU-216 gastric cancer cells, and HER2-negative MCF-7 breast cancer cells by serial centrifugations including two ultracentrifugations, and treated with T-DM1. T-DM1 not bound to exosomes was removed using HER2-coated magnetic beads. Exosome samples were analyzed by electron microscopy, flow cytometry and Western blotting. Binding of T-DM1-containing exosomes to cancer cells and T-DM1 internalization were investigated with confocal microscopy. Effects of T-DM1-containg exosomes on cancer cells were investigated with the AlamarBlue cell proliferation assay and the Caspase-Glo 3/7 caspase activation assay. Results: T-DM1 binds to exosomes derived from HER2-positive cancer cells, but not to exosomes derived from HER2-negative MCF-7 cells. HER2-positive SKBR-3 cells accumulated T-DM1 after being treated with T-DM1-containg exosomes, and treatment of SKBR-3 and EFM-192A cells with T-DM1-containing exosomes resulted in growth inhibition and activation of caspases 3 and/or 7. Conclusion: T-DM1 binds to exosomes derived from HER2-positive cancer cells, and T-DM1 may be carried to other cancer cells via exosomes leading to reduced viability of the recipient cells. The results suggest a new mechanism of action for T-DM1, mediated by exosomes derived from HER2-positive cancer.
  • Galli, Emilia; Lindholm, Päivi; Kontturi, Leena-Stiina; Saarma, Mart; Urtti, Arto; Yliperttula, Marjo (2019)
    Cerebral Dopamine Neurotrophic Factor (CDNF) shows beneficial effects in rodent models of Parkinson?s and Alzheimer?s disease. The brain is a challenging target for protein therapy due to its exclusive blood?brain barrier. Hence, the therapeutic protein should be delivered directly to the brain parenchyma. Implantation of encapsulated mammalian cells that constantly secrete CDNF is a potential approach for targeted and long-term protein delivery to the brain. In this study, we generated several CDNF-secreting cell clones derived from human retinal pigment epithelial cell line ARPE-19, and studied CDNF secretion from the clones maintained as monolayers and in polymeric microcapsules. The secretion of wild type (wt) CDNF transgene was low and the majority of the produced protein remained intracellular, locating mainly to the endoplasmic reticulum (ER). The secretion of wtCDNF decreased to even lower levels when the clones were in a non-dividing state, as in the microcapsules. Both codon optimization and deletion of the putative ER-retrieval signal (four last amino acids: KTEL) improved CDNF secretion. More importantly, the secretion of KTEL-deleted CDNF remained constant in the non-dividing clones. Thus, cells expressing KTEL-deleted CDNF, in contrast to wtCDNF, can be considered for cell encapsulation applications if the KTEL-deleted CDNF is proven to be biologically active in vivo.
  • Prabhakar, Neeraj; Merisaari, Joni; Le Joncour, Vadim; Peurla, Markus; Sen Karaman, Didem; Casals, Eudald; Laakkonen, Pirjo; Westermarck, Jukka; Rosenholm, Jessica M. (2021)
    Glioblastoma (GB) is the most frequent malignant tumor originating from the centralnervous system. Despite breakthroughs in treatment modalities for other cancer types, GB remainslargely irremediable due to the high degree of intratumoral heterogeneity, infiltrative growth, andintrinsic resistance towards multiple treatments. A sub-population of GB cells, glioblastoma stem cells(GSCs), act as a reservoir of cancer-initiating cells and consequently, constitute a significant challengefor successful therapy. In this study, we discovered that PEI surface-functionalized mesoporoussilica nanoparticles (PEI-MSNs), without any anti-cancer drug, very potently kill multiple GSClines cultured in stem cell conditions. Very importantly, PEI-MSNs did not affect the survival ofestablished GB cells, nor other types of cancer cells cultured in serum-containing medium, even at25 times higher doses. PEI-MSNs did not induce any signs of apoptosis or autophagy. Instead, asa potential explanation for their lethality under stem cell culture conditions, we demonstrate thatthe internalized PEI-MSNs accumulated inside lysosomes, subsequently causing a rupture of thelysosomal membranes. We also demonstrate blood–brain-barrier (BBB) permeability of the PEI-MSNs in vitroandin vivo. Taking together the recent indications for the vulnerability of GSCs for lysosomaltargeting and the lethality of the PEI-MSNs on GSCs cultured under stem cell culture conditions,the results enforcein vivotesting of the therapeutic impact of PEI-functionalized nanoparticles infaithful preclinical GB models.
  • Liu, Zehua; Li, Yunzhan; Li, Wei; Lian, Wenhua; Kemell, Marianna; Hietala, Sami; Figueiredo, Patricia; Li, Li; Mäkilä, Ermei; Ma, Ming; Salonen, Jarno; Hirvonen, Jouni T.; Liu, Dongfei; Zhang, Hongbo; Deng, Xianming; Santos, Helder A. (2019)
    Here, an oxidation/acid dual-responsive nanohybrids/ark system was produced. The microfluidics-produced nanohybrids endow the system with an orchestrated cascade from wound detection, reactive oxygen species scavenging, drug release to hydrogel formation. The drug release behavior imitates the dynamic wound healing process, thus rendering an enhanced bio-mimetic regeneration.
  • Annual Capri Workshop Grp; Glasier, Anna; Bhattacharya, Siladitya; Heikinheimo, Oskari; Volpe, Annibale (2019)
    Whatever the outcome, pregnancy provides the opportunity to offer effective contraception to couples motivated to avoid another pregnancy. This narrative review summarizes the evidence for health providers, drawing attention to current guidelines on which contraceptive methods can be used, and when they should be started after pregnancy, whatever its outcome. Fertility returns within 1 month of the end of pregnancy unless breastfeeding occurs. Breastfeeding, which itself suppresses fertility after childbirth, influences both when contraception should start and what methods can be used. Without breastfeeding, effective contraception should be started as soon as possible if another pregnancy is to be avoided. Interpregnancy intervals of at least 6 months after miscarriage and 1-2 years after childbirth have long been recommended by the World Health Organization in order to reduce the chance of adverse pregnancy outcome. Recent research suggests that this may not be necessary, at least for healthy women
  • Ambrosio, Elena; Podmore, Adrian; dos Santos, Ana L. Gomes; Magarkar, Aniket; Bunker, Alex; Caliceti, Paolo; Mastrotto, Francesca; van der Walle, Christopher F.; Salmaso, Stefano (2018)
    Peptide therapeutics have the potential to self-associate, leading to aggregation and fibrillation. Noncovalent PEGylation offers a strategy to improve their physical stability; an understanding of the behavior of the resulting polymer/ peptide complexes is, however, required. In this study, we have performed a set of experiments with additional mechanistic insight provided by in silico simulations to characterize the molecular organization of these complexes. We used palmitoylated vasoactive intestinal peptide (VIP-palm) stabilized by methoxy-poly(ethylene glycol)(skDa)-cholane (PEG-cholane) as our model system. Homogeneous supramolecular assemblies were found only when complexes of PEG-cholane/VIP-palm exceeded a molar ratio of 2:1; at and above this ratio, the simulations showed minimal exposure of VIP-palm to the solvent. Supramolecular assemblies formed, composed of, on average, 9-11 PEG-cholane/VIP-palm complexes with 2:1 stoichiometry. Our in silico results showed the structural content of the helical conformation in VIP-palm increases when it is complexed with the PEG-cholane molecule; this behavior becomes yet more pronounced when these complexes assemble into larger supramolecular assemblies. Our experimental results support this: the extent to which VIP-palm loses helical structure as a result of thermal denaturation was inversely related to the PEG-cholane:VIP-palm molar ratio. The addition of divalent buffer species and increasing the ionic strength of the solution both accelerate the formation of VIP-palm fibrils, which was partially and fully suppressed by 2 and >4 mol equivalents of PEG-cholane, respectively. We conclude that the relative freedom of the VIP-palm backbone to adopt nonhelical conformations is a key step in the aggregation pathway.
  • Ramsay, Eva; del Amo, Eva M.; Toropainen, Elisa; Tengvall-Unadike, Unni; Ranta, Veli-Pekka; Urtti, Arto; Ruponen, Marika (2018)
    On the surface of the eye, both the cornea and conjunctiva are restricting ocular absorption of topically applied drugs, but barrier contributions of these two membranes have not been systemically compared. Herein, we studied permeability of 32 small molecular drug compounds across an isolated porcine cornea and built a quantitative structure-property relationship (QSPR) model for the permeability. Corneal drug permeability (data obtained for 25 drug molecules) showed a 52-fold range in permeability (0.09-4.70x10(-6) cm/s) and the most important molecular descriptors in predicting the permeability were hydrogen bond donor, polar surface area and halogen ratio. Corneal permeability values were compared to their conjunctival drug permeability values. Ocular drug bioavailability and systemic absorption via conjunctiva were predicted for this drug set with pharmacokinetic calculations. Drug bioavailability in the aqueous humour was simulated to be <5% and trans-conjunctival systemic absorption was 34-79% of the dose. Loss of drug across the conjunctiva to the blood circulation restricts significantly ocular drug bioavailability and, therefore, ocular absorption does not increase proportionally with the increasing corneal drug permeability.
  • Luchkina, Natalia V.; Huupponen, Johanna; Clarke, Vernon R. J.; Coleman, Sarah K.; Keinanen, Kari; Taira, Tomi; Lauri, Sari E. (2014)