Polymeric Micelles in Ocular Drug Delivery: Rationale, Strategies and Challenges

Polymeric micelles that can deliver drug to intended sites of the eye have attracted much scientific attention recently. The aim here is to review the aqueous-based formulation of drug loaded polymeric micelles that hold significant promise for ophthalmic drug delivery. These innovative nanosystems can provide the biopharmaceutical advantages of higher permeation and enhancement of residence time at ocular surface for better drug absorption through ocular barriers. Mucoadhesive properties of biopolymers forming micelle enhance their contact time and minimize their elimination from the absorbing surface, consequently increasing the bioavailability of the drug. Their physicochemical characteristics are also important with respect to the industrial production and patient compliance. Drug loaded polymeric micelles can be fabricated by simple and cost effective techniques with improved physical stability which fulfils the requirements for industrial acceptance. Innovative polymeric micelle formulations allow their easy application in the form of eye drops without blurring of vision and discomfort, thus achieving patient compliance requirements

Sinteza konjugata fenoprofena i gemfibrozila s kopolimerom stirena i maleinske kiseline

Two types of polymer-drug conjugates were synthesized starting from styrene-maleic acid anhydride copolymer (SMA). Fenoprofen and gemfibrozil were chosen as model drugs because of their short plasma half lives. Both drugs were first converted to their 2-aminoethylamides, which possess free amino groups capable of reacting with SMA anhydride rings. By modifying the degree and type of substitution, lipophilic and hydrophilic conjugates were obtained. Drug loading in the conjugates was between 17 and 47%.U radu je opisana sinteza polimer-lijek konjugata polazeći od kopolimera stirena i anhidrida maleinske kiseline (SMA) i fenoprofena, odnosno gemfibrozila, ljekovitih tvari s kratkim vremenom zadržavanja u plazmi. Fenoprofen i gemfibrozil su prvo prevedeni u 2-aminoetilamide, koji su zbog slobodne amino skupine mogli reagirati s anhidridnim prstenovima u SMA. Modifikacijom tipa i vrste supstitucije pripravljeni su lipofilni i hidrofilni konjugati. Udio vezanog lijeka u konjugatima bio je između 17 and 47%

Spray-driedMicrospheres Based on Chitosan and LecithinCyclosporin A Delivery System

Conventional and composed cyclosporin A (CsA)-loaded polymeric microspheres (MS) were prepared by spray-drying of CsA/chitosan one-phase system (solutions) and CsA/lecithin/chitosan two-phase system (suspensions). Microspheres were characterised in terms of production yield, entrapment efficiency, size distribution, zeta-potential, thermal properties, swelling ability and drug release profile. Conventional MS were characterised by mean diameter ranging from 1.15 ± 0.91 to 1.27 ± 0.84 m and CsA entrapment efficiency varying from 72.6 to 87.3%. Composed MS were characterised by larger mean diameter (1.32 ± 1.08 to 1.53 ± 1.15 m) and higher CsA entrapment efficiency (86.6–94.3%) compared to the corresponding conventional MS. Only composed MS showed swelling ability, which was proportional to chitosan base content in the preparation. In vitro CsA release profile depended on both, the type of the spray-dried system and the chitosan used, as these factors were crucial in determining CsA entrapment pattern and swelling/dissolution ability of MS

D-Optimal Design in the Development of Rheologically Improved In Situ Forming Ophthalmic Gel

In situ forming ophthalmic gels need to be fine tuned considering all the biopharmaceutical challenges of the front of the eye in order to increase drug residence time at the application site resulting in its improved bioavailability and efficacy. The aim of this study was to develop in situ forming ophthalmic poloxamer P407/poloxamer P188/chitosan gel fine tuned in terms of polymer content, temperature of gelation, and viscosity. Minimizing the total polymer content while retaining the advantageous rheological properties has been achieved by means of D-optimal statistical design. The optimal in situ forming gel was selected based on minimal polymer content (P407, P188, and chitosan concentration of 14.2%, 1.7%, and 0.25% w/w, respectively), favorable rheological characteristics, and in vitro resistance to tear dilution. The optimal in situ forming gel was proved to be robust against entrapment of active pharmaceutical ingredients making it a suitable platform for ophthalmic delivery of active pharmaceutical ingredients with diverse physicochemical properties

Azithromycin-liposomes as a novel approach for localized therapy of cervicovaginal bacterial infections

Background: Efficient localized cervicovaginal antibacterial therapy, enabling the delivery of antibiotic to the site of action at lower doses while escaping systemic drug effects and reducing the risk of developing microbial resistance, is attracting considerable attention. Liposomes have been shown to allow sustained drug release into vaginal mucosa and improve delivery of antibiotics to bacterial cells and biofilms Azithromycin (AZI), a potent broad-spectrum macrolide antibiotic, has not yet been investigated for localized therapy of cervicovaginal infections, although it is administered orally for the treatment of sexually transmitted diseases. Encapsulation of AZI in liposomes could improve its solubility, antibacterial activity, and allow the prolonged drug release in the cervicovaginal tissue, while avoiding systemic side effects. Purpose: The objective of this study was to develop AZI-liposomes and explore their potentials for treating cervicovaginal infections. Methods: AZI-liposomes that differed in bilayer elasticity/rigidity and surface charge were prepared and evaluated under simulated cervicovaginal conditions to yield optimized liposomes, which were assessed for antibacterial activity against several planktonic and biofilm-forming Escherichia coli strains and intracellular Chlamydia trachomatis, ex vivo AZI vaginal deposition/penetration, and in vitro cytotoxicity toward cervical cells. Results: Negatively charged liposomes with rigid bilayers (CL-3), propylene glycol liposomes (PGL-2) and deformable propylene glycol liposomes (DPGL-2) were efficient against planktonic E. coli ATCC 700928 and K-12. CL-3 was superior for preventing the formation of E. coli ATCC 700928 and K-12 biofilms, with IC50 values (concentrations that inhibit biofilm viability by 50%) up to 8-fold lower than those of the control (free AZI). DPGL-2 was the most promising for eradication of already formed E. coli biofilms and for treating C. trachomatis infections. All AZI-liposomes were biocompatible with cervical cells and improved localization of the drug inside vaginal tissue compared with the control. Conclusion: The performed studies confirm the potentials of AZI-liposomes for localized cervicovaginal therapy.Peer reviewe

Prevalence, prenatal screening and neonatal features in children with Down syndrome: a registry-based national study

BACKGROUND: Down syndrome (DS) is one of the most common chromosomal abnormalities among newborns. In recent years advances in perinatal and neonatal care have improved chance of survival for the children with DS. The objective of this Registry-Based study was to get more accurate data of DS prevalence with evaluation of antenatal screening, neonatal and maternal features among total births in Croatia from 2009 to 2012. ----- METHODS: We used retrospectively collected data for DS newborns from the medical birth database and perinatal mortality database for the period of 2009-2012. Differences between DS and the referent population for each year in quantitative measures were assessed with the independent t-test. Other differences in nominal and categorical values were analyzed with the chi-square test. ----- RESULTS: The total prevalence for DS in the period of 2009-2012 was 7.01 per 10,000 births, while the live-birth prevalence was 6.49 per 10,000 births. The significant differences (p < 0.05) between the DS and reference populations for each year were noticed for birth weight and length, gestational age, mother age, Apgar score of ≥6 after 5 min and breastfeeding. Among newborns with DS, there were 64 (53.33 %) males and 56 (46.67 %) females versus 88,587 (51.76 %) males and 82,553 (48.23 %) females in the reference population. In the DS group compared to the reference population the mean birth weight was 2845 grams versus 3467 grams in males and 2834 grams versus 3329 grams in females, respectively, with a mean birth length of 47 cm versus 50 cm for both genders. The mean gestational age of the DS births was 37 weeks and the mean age of the mothers was 32.6 years, versus 39 weeks and 29.1 years, respectively, in the reference population. Only 68.3 % of children with DS were breastfed from birth, compared with 94.72 % of children in the reference population. ----- CONCLUSIONS: The significant differences for neonatal and maternal features between DS and the referent population were found similar to other studies. The total prevalence of DS in Croatia in the period of 2009-2012 was lower than the previously estimated prevalence based on EUROCAT data. The establishment of a new national registry of congenital malformations covering 99 % of all births in Croatia is necessary to improve the health and prosperity of children, adolescents and adults with DS in Croatia

The stabilization and release performances of curcumin-loaded liposomes coated by high and low molecular weight chitosan

A comprehensive stability evaluation for curcumin-loaded liposomes (Cur-LP) coated by low (LCS) or high (HCS) molecular weight chitosan with three gradient concentrations (L: low; M: medium; H: high) was the main objective of this study. Apart from leading to a higher encapsulation efficiency (>90%), all chitosan-coated Cur-LP displayed an improved stability with respect to resistant to salt, sunlight, heat, accelerated centrifugation and long-term storage at 4 °C. Increasing the molecular weight and concentration of chitosan could effectively improve the stability of Cur-LP, in which HCS-H coatings displayed the best performance. According to the fluorescence probe analysis, the mechanical reinforcement of liposomes and the concomitant reduction in membrane fluidity accounts for the major contribution to vesicle stability. Secondly, a simulated digestion model was used to prove the applicability of sustained curcumin release, achieved by adjusting the molecular weight and concentration of the chitosan stabilizer for Cur-LP. The results of this study show that high molecular weight chitosan used at relatively high concentrations, is a promising coating material for improving the stability and sustained release of Cur-LP in vitro