Eye Drop Formulation Research Articles

Polymeric Micelles for the Enhanced Deposition of Hydrophobic Drugs into Ocular Tissues, without Plasma Exposure.

Commercial topical ocular formulations for hydrophobic actives rely on the use of suspensions or oil in water emulsions and neither of these formulation modalities adequately promote drug penetration into ocular tissues. Using the ocular relevant hydrophobic drug, cyclosporine A (CsA), a non-irritant ocular penetration enhancer is showcased, which may be used for the formulation of hydrophobic actives. The activity of this penetration enhancer is demonstrated in a healthy rabbit model. The Molecular Envelope Technology (MET) polymer (N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan), a self-assembling, micelle-forming polymer, was used to formulate CsA into sterile filtered nanoparticulate eye drop formulations and the stability of the formulation tested. Healthy rabbits were dosed with a single dose of a MET–CsA (NM133) 0.05% formulation and ocular tissues analyzed. Optically clear NM133 formulations were prepared containing between 0.01–0.1% w/v CsA and 0.375–0.75% w/v MET polymer. NM133 0.01%, NM133 0.02% and NM133 0.05% were stable for 28 days when stored at refrigeration temperature (5–6 °C) and room temperature (16–23 °C), but there was evidence of evaporation of the formulation at 40 °C. There was no change in drug content when NM133 0.05% was stored for 387 days at 4 °C. On topical dosing to rabbits, corneal, conjunctival and scleral AUC0–24 levels were 25,780 ng.h g−1, 12,046 ng.h g−1 and 5879 ng.h g−1, respectively, with NM133 0.05%. Meanwhile, a similar dose of Restasis 0.05% yielded lower values of 4726 ng.h/g, 4813 ng.h/g and 1729 ng.h/g for the drug corneal, conjunctival and scleral levels, respectively. NM133 thus delivered up to five times more CsA to the ocular surface tissues when compared to Restasis. The MET polymer was non-irritant up to a concentration of 4% w/v. The MET polymer is a non-irritant ocular penetration enhancer that may be used to deliver hydrophobic drugs in optically clear topical ocular formulations.

Assessment of a New Nanostructured Microemulsion System for Ocular Delivery of Sorafenib to Posterior Segment of the Eye.

Eye drop formulations allowing topical treatment of retinal pathologies have long been sought as alternatives to intravitreal administration. This study aimed to assess whether a novel nanostructured microemulsions system (NaMESys) could be usefully employed to deliver sorafenib to the retina following topical instillation. NaMESys carrying 0.3% sorafenib (NaMESys-SOR) proved to be cytocompatible in vitro on rabbit corneal cells, and well-tolerated following b.i.d. ocular administration to rabbits during a 3-month study. In rats subject to retinal ischemia-reperfusion, NaMESys-SOR significantly inhibited retinal expression of tumor necrosis factor-alpha (TNFα, 20.7%) and inducible nitric oxide synthase (iNos, 87.3%) mRNAs in comparison to controls. Similarly, in streptozotocin-induced diabetic rats, NaMESys-SOR inhibited retinal expression of nuclear factor kappa B (NFκB), TNFα, insulin like growth factor 1 (IGF1), IGF1 receptor (IGF1R), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2) mRNAs by three-fold on average compared to controls. Furthermore, a reduction in TNFα, VEGFR1 and VEGFR2 protein expression was observed by western blot. Moreover, in mice subject to laser-induced choroidal neovascularization, NaMESys-SOR significantly inhibited neovascular lesions by 54%. In conclusion, NaMESys-SOR was shown to be a well-tolerated ophthalmic formulation able to deliver effective amounts of sorafenib to the retina, reducing proinflammatory and pro-angiogenic mediators in reliable models of proliferative retinopathies. These findings warrant further investigations on the full therapeutic potential of NaMESys-SOR eye drops, aiming to address unmet needs in the pharmacotherapy of retinal neovascular diseases.

Ингибиторы ангиотензин-превращающего фермента в составе кальций-фосфатных наночастиц как перспективные препараты для снижения внутриглазного давления

Purpose. To find out the possibility of using angiotensin-converting enzyme (ACE) inhibitors included in calcium-phosphate nanoparticles (CFPs) to reduce intraocular pressure (IOP). Material and methods. Preparation of calcium-phosphate nanoparticles, introduction of ACEI in them, comparative evaluation of the action of enalaprilat, lisinopril and the beta-blocker timolol in the composition of CPF by determining their effect on intraocular pressure in rabbits. Results. Enalaprilat, lisinopril and the beta-blocker timolol in the composition of CPF statistically more significantly reduce intraocular pressure compared to simple solutions of these drugs. Conclusion. The introduction of drugs that reduce IOP into the CPF increases their bioavailability with the instillation method of administration, while their biological activity is preserved, and the effectiveness of the therapeutic effect increases. The results indicates the prospects of using CFPs to include ocular antihypertensive drugs used in the form of eye drops. Key words: calcium-phosphate nanoparticles, angiotensin-converting enzyme inhibitor, intraocular pressure.

Aqueous eye drops containing drug/cyclodextrin nanoparticles deliver therapeutic drug concentrations to both anterior and posterior segment.

Using topical application to deliver therapeutic concentrations of drugs to the posterior segment of the eye remains very challenging. As a result, posterior segment diseases are usually treated by intravitreal injection or implant. While topical treatments are commonly used for anterior segment conditions, they sometimes require frequent applications. Eye drop formulations based on γ-cyclodextrin (γCD)-based nanoparticle aggregates were developed, which in animal models and clinical studies deliver therapeutic concentrations of drugs (dorzolamide and dexamethasone) to both anterior and posterior segments of the eye. An early study in humans showed dorzolamide/γCD eye drops could achieve comparable intraocular pressure decreases to commercial dorzolamide eye drops, but with less frequent application. Pilot studies with dexamethasone/γCD eye drops suggested that they could be effective in a range of conditions, including diabetic macular oedema, cystoid macular oedema and vitritis secondary to uveitis, postcataract surgery inflammation and postoperative treatment in trabeculectomy. Phase II studies with similar dexamethasone/γCD nanoparticle eye drops in diabetic macular oedema and postcataract surgery inflammation have recently been completed. This technology has the potential to be used with other classes of drug molecules and to replace or complement invasive treatments, providing safer, non-invasive therapies, particularly for posterior segment conditions, that can be self-administered as eye drops by patients.

ИССЛЕДОВАНИЕ ОСМОЛЯЛЬНОСТИ И ИЗОГИДРИЧНОСТИ ГЛАЗНЫХ КАПЕЛЬ ЭКСТЕМПОРАЛЬНОГО ИЗГОТОВЛЕНИЯ

Aim. Analysis of osmolality and isohydricity of eye drops of extemporaneous manufacture for compliance with the requirements of the normative documents. Materials and Methods. The object of study was eye drops of extemporaneous manufacture according to formulations and technologies of the normative documents. To control determination of the permissible limits of osmolality, model eye drops with sodium chloride at concentration of 0.6%, 0.9%, 2.0% were manufactured. Osmolality of the eye drops was determined by a pharmacopeian method using МТ-5 thermoelectric milliosmometracryoscope. pH was measured by a method of ionometry using HANNA microprocessor pH/C meter. The results were statistically processed. Results. It was found that eye drops 2%, 3% collargol and 1% sodium thiosulfate solution do not comply with the normative parameters by osmolality. Such drops as 0.2% ascorbic acid; combined eye drops containing riboflavin, ascorbic acid and boric acid; riboflavin, ascorbic acid and glucose did not comply with the normative parameters by pH value. These drops have a strong shift of pH towards acidity. The value of pH was below 3.5. On the contrary, eye drops containing sodium hydrocarbonate, sodium tetraborate have an exceeding shift towards alkalinity with pH more than 8.5. Thus, the conducted study showed the necessity of introduction of certain changes to the composition of the above mentioned eye drops after consultation with ophthalmologists. Conclusion. In the work, technological and analytical study of osmolality and isohydricity of some official compositions of eye drops encountered in extemporaneous manufacture, was conducted. Using modern pharmacopeian methods, the mentioned parameters of eye drops were determined and compared with the normative parameters recommended by the governmental quality standards of General Pharmacopeia Monograph (GPM) «Ophthalmic Dosage Forms», and the necessity for correction of certain formulations of eye drops is shown.

The effects of addition of functional monomers and molecular imprinting on dual drug release from intraocular lens material

Although cataract surgery is considered a safe procedure, post-surgery complications such as endophthalmitis and ocular inflammation, may occur. To prevent this, antibiotics and anti-inflammatories are prescribed in the form of eye drops during the post-operatory period, but they lead to a low drug bioavailability in target tissues. The objective of this work is to develop an intraocular lens (IOL) material to deliver simultaneously one antibiotic, moxifloxacin (MXF), and one anti-inflammatory, diclofenac (DFN), in therapeutic concentrations to prevent both complications. The IOL material was modified through the incorporation of functional monomers, as well as molecular imprinting with both drugs using the same functional monomers, namely acrylic acid (AA), methacrylic acid (MAA), 4-vinylpiridine (4-VP) and a combination of MAA + 4-VP. The best results were obtained with MAA. Molecular imprinting did not influence the drug release, except with AA. Application of a mathematical model predicted that the released MXF and DFN concentrations would stay above the pre-determined MIC of S. aureus and S. epidermidis and the minimum values of IC50 of COX-1 and COX-2, for 9 and 14 days, respectively. Antibacterial tests showed that the released antibiotic remained active. The physical properties of the drug-loaded MAA-hydrogel remained adequate. The developed system proved to be non-irritant and non-cytotoxic.

Scientific substantiation of the concentration of excipients for the manufacture of eye drops Angiolin

Throughout human history, cataracts have been one of the leading causes of blindness. For this disease, we studied the market of drugs of domestic and foreign production.
 The object of our study was the subgroup S10X Other ophthalmic drugs. Employees of the Department of Pharmaceutical Chemistry of Zaporizhzhia State Medical University (ZSMU) together with specialists of the NGO “Pharmatron” was synthesized a new compound, which was named Angiolin. A rational dosage form in the form of eye drops was proposed for the new drug. Since the drops continue to be the most common and widely used in practice dosage form.
 We have previously selected the optimal content of the active substance in eye drops. As is known from the technological parameters, eye drops must be isotonic, ie in their composition should be added excipients.
 The aim of our work is to select the concentration of excipients for the manufacture of eye drops Angiolin.
 Materials and methods. During the work at the Department of Pharmaceutical Chemistry of ZSMU, three solutions of eye drops Angiolin with different composition were prepared, and later the theoretical osmolarity was calculated.
 Results. Accurate theoretical calculation of the osmolarity of solutions containing substances with high molecular weight, complex total extracts, and highly concentrated solutions is impossible. Since the excipient was used methylcellulose, it was better to perform such a calculation experimentally, through the determination of osmolality. On the basis of the conducted researches, for correction of osmolarity, we were chosen – sodium chloride. Sodium chloride was selected at a concentration of 7.0 g/l, which creates an osmolality of the drug equal to 234.3 mosmol/kg. The estimated value at the same concentration of sodium chloride was 239.56 mosmol/l. The value of osmolarity of eye drops was calculated from it makes 302,18 mosmol/l that was confirmed the correctness of the chosen concentration of sodium chloride as a part of eye drops.
 Conclusions. Based on the above, we selected the concentration of excipients for the manufacture of eye drops Angiolin.

Feline thelaziosis (Thelazia callipaeda) in Spain: state-of-the-art and first prophylactic trial in cats.

Thelaziosis caused by the nematode Thelazia callipaeda (Spirurida, Thelaziidae) affects the eyes of domestic and wild carnivores, lagomorphs and even humans. The role of cats in spreading thelaziosis remains unclear. The present study assesses the current status of feline T callipaeda infection in Spain and presents the results of the first prophylactic trial conducted in this species. We retrospectively analysed the occurrence of feline thelaziosis (study 1), examined its prevalence based on cross-sectional sampling of endemic areas (study 2), and assessed the therapeutic/prophylactic benefits of a spot-on (moxidectin) and therapeutic efficacy of an eye drop (ivermectin) formulation (study 3). In study 1, 69 Thelazia-infected cats were examined. Autochthonous cases were detected in 18/26 municipalities surveyed in Spain, which corresponds to 88.4% (n = 61/69) of the total number of cases. In study 2, 74 cats (20 from La Vera region and 54 from Orense province) were examined from 2011 to 2013. Ten of these cats (13.5%) were infected with T callipaeda. The infection prevalence was 40% (n = 8/20) in La Vera and 3.7% (n = 2/54) in Orense. The therapeutic efficacy of ivermectin was assessed over a summer (2011) in 12 cats, while that of moxidectin was examined over a 17-month period in seven cats. Four of these seven cats were subsequently included in an all-year-round prophylaxis trial. Treatment efficacy ranged from 91.7% (ivermectin) on day 28 after treatment to 100% (moxidectin) on day 14. Moxidectin prevented reinfections in cats. Our data confirm the endemic status of T callipaeda infection in Spain, revealing its high prevalence in cats living in known endemic areas. Moxidectin was effective in treating and preventing infection. We strongly recommend the inclusion of thelaziosis in the differential diagnosis of pets and humans presenting with ocular manifestations, along with adequate preventive measures.

To study the role of platelet rich plasma as treatment in various etiologies of dry eye

To evaluate the effect of platelet rich plasma as treatment modality in various etiologies of dry eye.: A prospective study was conducted at a tertiary eye care hospital on 65 eyes of 40 patients for a duration of three years, who presented with the complaints of dry eye due to various etiologies. Platelet rich plasma (PRP) was made from the patient’s serum and they were advised to be instilled in topical eyedrop form six times a day. The study included 29 men and 11 women. The mean age was 40yrs (34.45±15.17), range 10 – 60 years. Dry eye symptoms like burning sensation, itching, dryness, blurred vision and redness were studied and were found to be significantly reduced (p=0.0001)post treatment with PRP after one month. The improvement in symptoms was most likely due to indirect reduction of inflammation. Around 30.7% eyes had improvement in visual acuity of atleast one line. The Schirmer’s test also showed improvement with Schirmer values before treatment being 5.34mm± 2.18 mm to 15.90 mm±7.75mm after treatment. Around 46.87% right eye and 39.9% left eye also had improvement with tear break up time more than 10 sec.The use of PRP eye drops for the treatment of various etiologies of dry eye was shown to be effective in reducing the symptoms of dry eye without any significant complications.

Review of Approaches for Increasing Ophthalmic Bioavailability for Eye Drop Formulations.

Ophthalmic diseases represent a significant problem as over 2 billion people worldwide suffer from vison impairment and blindness. Eye drops account for around 90% of ophthalmic medications but are limited in success due to poor patient compliance and low bioavailability. Low bioavailability can be attributed to short retention times in the eye caused by rapid tear turnover and the difficulty of drug diffusion through the multi-layered structure of the eye that includes lipid-rich endothelial and epithelial layers as well as the stroma which is high in water content. In addition, there are barriers such as tight junctional complexes in the corneal epithelium, lacrimal turnover, nasolacrimal drainage, blinking reflexes, efflux transporters, drug metabolism by ocular enzymes, and drug binding to or repulsion from conjunctival mucins, tear proteins, and melanin. In order to maximize transport through the cornea while minimizing drug loss through other pathways, researchers have developed numerous methods to improve eye drop formulations including the addition of viscosity enhancers, permeability enhancers, mucoadhesives, and vasoconstrictors, or using formulations that include puncta occlusion, nanocarriers, or prodrugs. This review explains the mechanism behind each of these methods, examines their history, analyzes previous and current research, evaluates future applications, and discusses the pros and cons of each technique.

Clinical Application and Efficacy of Silver Drug in Ophthalmology: A Literature Review and New Formulation of EYE Drops with Drug Silver (I) Complex of Metronidazole with Improved Dosage Form.

The use of silver preparations in medicine is becoming increasingly popular. The basic aim of this evaluation was to review the literature on the clinical (in vivo) and antibacterial potential of silver preparations in ophthalmic diseases. The second goal was to summarize the results of experimental research on the use of silver preparations in ophthalmology. The third objective was to present a method for stabilizing eye drops containing silver (I) complex. Analysis of the pH stability of the silver (I) complex with metronidazole in the prepared dosage form (eye drops) was carried out. Most silver preparations are clinically used for topical application. Few experimental results indicate the usefulness of intraocular or systemic administration of silver (I) preparations as an alternative or additional therapy in infectious and angiogenic eye diseases. The development of a new formulation increases the stability of the dosage form. New forms of silver (I) products will certainly find application in the treatment of many ophthalmic diseases. One of the most important features of the silver (I) complex is its capacity to break down bacterial resistance. The new eye drops formula can significantly improve comfort of use. Due to their chemical nature, silver (I) compounds are difficult to stabilize, especially in the finished dosage form.

Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment-A Systematic Review.

There is an unmet clinical need for eye drop formulations to efficiently treat the diseases of the posterior ocular segment by non-invasive topical administration. Here, we systematically reviewed the literature on ocular penetration enhancers and their ability to transfer drugs to the posterior segment of the eye in experimental studies. Our aim was to assess which penetration enhancer is the most efficient at delivering drugs to the posterior segment of the eye, when topically applied. We conducted a comprehensive search in three electronic databases (Ovid Embase, Ovid MEDLINE, and PubMed) to identify all the relevant manuscripts reported on ocular penetration enhancers based on the PRISMA guidelines. We identified 6540 records from our primary database search and filtered them per our inclusion/exclusion criteria to select a final list of 14 articles for qualitative synthesis. Of these, 11 studies used cell penetrating peptides (CPPs), 2 used chitosan, and 1 used benzalkonium chloride (BAC) as the penetration enhancer. Cationic and amphipathic CPPs, transactivator of transcription (TAT), and penetratin can be inferred to be the best among all the identified penetration enhancers for drug delivery to the fundus oculi via topical eye drop instillation. Further high-quality experimental studies are required to ascertain their quantitative efficacy.

Use of Acellular Umbilical Cord-Derived Tissues in Corneal and Ocular Surface Diseases.

Blood derived products have become a valuable source of tissue for the treatment of ocular surface diseases that are refractory to conventional treatments. These can be obtained from autologous or allogeneic sources (patient’s own blood or from healthy adult donors/umbilical cord blood, respectively). Allogeneic cord blood demonstrates practical advantages over alternatives and these advantages will be discussed herein. Umbilical cord blood (UCB) can be divided, generally speaking, into two distinct products: first, mononuclear cells, which can be used in regenerative ophthalmology, and second, the plasma/serum (an acellular fraction), which may be used in the form of eyedrops administered directly to the damaged ocular surface. The rationale for using umbilical cord serum (UCS) to treat ocular surface diseases such as severe dry eye syndrome (DES), persistent epithelial defects (PED), recurrent epithelial erosions, ocular chemical burns, graft versus host disease (GVHD), among others, is the considerably high concentration of growth factors and cytokines, mimicking the natural healing properties of human tears. Allogeneic serum also offers the opportunity for therapeutic treatment to patients who, due to poor heath, cannot provide autologous serum. The mechanism of action involves the stimulation of endogenous cellular proliferation, differentiation and maturation, which is highly efficient in promoting and enhancing corneal epithelial healing where other therapies have previously failed.

A polymeric aqueous tacrolimus formulation for topical ocular delivery

Tacrolimus (TAC) suspension is used to treat moderate to severe atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). The objectives of this study were to formulate the hydrophobic compound TAC (TAC) in an aqueous eye drop formulation and study its ocular biodistribution on topical ocular application to a healthy rabbit model, with the overall aim of using the formulation to treat AKC and VKC. A thin-film hydration method was used to encapsulate TAC within the chitosan-based amphiphile: N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (Molecular Envelope Technology – MET) in an aqueous formulation. The formulation was characterized, and its stability studied under three storage conditions for one month. The ocular distribution of the formulation was studied in healthy rabbits and the ocular tissues and the whole blood analyzed by LC-MS/MS. A 200 nm nanoparticle formulation (MET-TAC) containing 0.1 ± 0.002% w/v TAC was produced with viscosity, osmolarity and pH within the ocular comfort range, and the formulation was stable on refrigeration for one month. On topical application, the TAC concentrations in rabbit cornea and conjunctiva one hour after dosing were 4452 ± 2289 and 516 ± 180 ng/g of tissue, respectively. A topical ocular aqueous TAC eye drop formulation has been prepared with the ability to deliver sufficient drug to the relevant ocular surface tissues.

New Approach in Ocular Drug Delivery: In vitro and ex vivo Investigation of Cyclodextrin-Containing, Mucoadhesive Eye Drop Formulations.

BackgroundOptimal transcorneal penetration is necessary for ocular therapy; meanwhile, it is limited by the complex structure and defensive mechanisms of the eye. Antimicrobial stability of topical ophthalmic formulations is especially important. According to previous studies, the mostly used preservative, benzalkonium-chloride is irritative and toxic on corneal epithelial cells; therefore, novel non-toxic, antimicrobial agents are required. In this study, prednisolone-containing ophthalmic formulations were developed with expected optimal permeation without toxic or irritative effects.MethodsThe toxicity and permeability of prednisolone-containing eye drops were studied on a human corneal epithelial cell line (HCE-T) and ex vivo cornea model. The lipophilic drug is dissolved by the formation of cyclodextrin inclusion complex. Zinc-containing mucoadhesive biopolymer was applied as an alternative preservative agent, whose toxicity was compared with benzalkonium-chloride.ResultsAs the results show, benzalkonium-chloride-containing samples were toxic on HCE-T cells. The biopolymer caused no cell damage after the treatment. This was confirmed by immunohistochemistry assay. The in vitro permeability was significantly higher in formulations with prednisolone-cyclodextrin complex compared with suspension formulation. According to the ex vivo permeability study, the biopolymer-containing samples had significantly lower permeability.ConclusionConsidering the mucoadhesive attribute of target formulations, prolonged absorption is expected after application with less frequent administration. It can be stated that the compositions are innovative approaches as novel non-toxic ophthalmic formulations with optimal drug permeability.

Regenerative Therapy Using Umbilical Cord Serum.

Regenerative medicine is a branch of medicine that incorporates tissue-engineering, biomaterials, and cell therapy approaches to replace or repair damaged cells and tissues. Umbilical cord serum (UCS) is an important liquid component of cord blood, which has a reliable source of innumerable growth factors and biologically active molecules. Usually, serum can be prepared from different sources of blood. In therapeutic application, cord serum can be prepared and used in the form of eye drops for the treatment of severe dry eye diseases, ocular burns, glaucoma, persistent corneal epithelial defects and neurotrophic keratitis. In addition, cord serum combined with synthetic bio scaffold materials is used to regenerate different types of tissues including tympanic membrane regeneration, bone regeneration and nerve regeneration. Absence of animal origin viruses and bacteria, lack of xenoproteins and cost-effective features make cord serum a feasible choice as replacement of fetal bovine serum in cell culture techniques. Thus, this review emphasizes the role of cord serum in regenerative therapy and clinical uses.

Formulation and Stability of Ataluren Eye Drop Oily Solution for Aniridia

Congenital aniridia is a rare and severe panocular disease characterized by a complete or partial iris defect clinically detectable at birth. The most common form of aniridia occurring in around 90% of cases is caused by PAX6 haploinsufficiency. The phenotype includes ptosis, nystagmus, corneal limbal insufficiency, glaucoma, cataract, optic nerve, and foveal hypoplasia. Ataluren eye drops aim to restore ocular surface PAX6 haploinsufficiency in aniridia-related keratopathy (ARK). However, there are currently no available forms of the ophthalmic solution. The objective of this study was to assess the physicochemical and microbiological stability of ataluren 1% eye drop in preservative-free low-density polyethylene (LDPE) bottle with an innovative insert that maintains sterility after opening. Because ataluren is a strongly lipophilic compound, the formulation is complex and involves a strategy based on co-solvents in an aqueous phase or an oily formulation capable of totally dissolving the active ingredient. The visual aspect, ataluren quantification by a stability-indicating chromatographic method, and microbiological sterility were analyzed. The oily formulation in castor oil and DMSO (10%) better protects ataluren hydrolysis and oxidative degradation and permits its complete solubilization. Throughout the 60 days period, the oily solution in the LDPE bottle remained clear without any precipitation or color modification, and no drug loss and no microbial development were detected. The demonstrated physical and microbiological stability of ataluren 1% eye drop formulation at 22–25 °C might facilitate clinical research in aniridia.

In situ Gelling Amphotericin B Nanofibers: A New Option for the Treatment of Keratomycosis

The purpose of our research was the development of Amphotericin B-loaded in situ gelling nanofibers for the treatment of keratomycosis. Different formulation strategies were applied to increase the drug load of the sparingly water-soluble Amphotericin B in electrospun Gellan Gum/Pullulan fibers. These include bile salt addition, encapsulation in poly(lactic-co-glycolic acid) (PLGA) nanoparticles and formation of a polymeric Amphotericin B polyelectrolyte complex. The Amphotericin B polyelectrolyte complex (AmpB-Eu L) performed best and was very effective against the fungal strain Issatchenkia orientalis in vitro. The complex was characterized in detail by attenuated total reflection infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. A heat induced stress test was carried out to ensure the stability of the polyelectrolyte complex. To gain information about the cellular tolerance of the developed polyelectrolyte complex a new, innovative multilayered-stratified human cornea cell model was used for determination of the cellular toxicity in vitro. For a safe therapy, the applied ophthalmic drug delivery system has to be sterile. Sterilization by electron irradiation caused not degradation of pure Amphotericin B and also for the bile salt complex. Furthermore, the developed Amphotericin B polyelectrolyte complex was not degraded by the irradiation process. In conclusion, a new polyelectrolyte Amphotericin B complex has been found which retains the antifungal activity of the drug with sufficient stability against irradiation-sterilization induced drug degradation. Furthermore, in comparison with the conventional used eye drop formulation, the new AmpB-complex loaded nanofibers were less toxic to cornea cells in vitro. Electrospinning of the Amphotericin B polyelectrolyte complex with Gellan Gum/ Pullulan leads to the formation of nanofibers with in situ gelling properties, which is a new and promising option for the treatment of keratomycosis.

Protective effects of PARP1-inhibitory compound in dry age-related macular degeneration

Poly (ADP-ribose) polymerase 1 (PARP1)-dependent cell death in the retinal pigment epithelium (RPE) is implicated in dry age-related macular degeneration (AMD). Although PARP1 inhibitors are available for treating dry AMD, their delivery route is not ideal for patients. The aim of this study was to test the efficacy of a novel PARP1-inhibitory compound (PIC) in vitro and in vivo. This study presents PIC, a novel small molecule, with superior efficacy to PARP1 inhibitors in the market. PIC demonstrated a distinctive inhibitory profile against PARP isotypes than the FDA-approved PARP1 inhibitors. PIC inhibited PARP1 activation at an IC50 of 0.41 ± 0.15 nM in an enzyme-based assay in vitro and at IC50 and EC50 in ARPE-19 cells of 0.11 ± 0.02 nM and 0.22 ± 0.02 nM, respectively, upon H2O2 insult. PIC also moderated mitochondrial fission and depolarization and maintained cellular energy levels under oxidative stress in ARPE-19 cells. Furthermore, PIC demonstrated good corneal penetration in a rat model, presenting PIC as a promising candidate for eye drop therapeutics for dry AMD. When PIC was administered as an eye drop formulation, RPE morphology was preserved, maintaining the thickness of the outer nuclear layers under sodium iodate (SI) treatment in rats. In SI-treated rabbits, eye drop administration of PIC also retained the structural and functional integrity when analyzed using funduscopy and electroretinogram. Collectively, our data portray PIC as an attractive treatment measure for dry AMD.

Curcumin In Situ Gelling Polymeric Insert with Enhanced Ocular Performance.

The search for an ocular drug delivery system that could provide long-acting effects without a detriment to the anatomy and physiology of the eye remains a challenge. Polyphenolic compounds (curcumin in particular) have recently gained popularity due to their powerful antioxidant properties; yet curcumin suffers poor stability and water solubility. A conventional eye drop formulation of curcumin in the form of a suspension is likely to suffer a short duration of action requiring multiple instillations. On the other hand, polymeric in-situ gelling inserts offer the prospect of overcoming these limitations. The aim of this study was to prepare, characterize and evaluate in vivo, polymeric, in-situ gelling and mucoadhesive inserts for ocular surface delivery of curcumin. Different types and ratios of biocompatible polymers (HPMC, CMC, PL 127 and PVA) and three plasticizers along with the solvent casting method were adopted to prepare curcumin inserts. The inserts were investigated for their physicochemical characteristics, applicability, and suitability of use for potential placement on the ocular surface. The prepared inserts revealed that curcumin was mainly dispersed in the molecular form. Insert surfaces remained smooth and uniform without cracks appearing during preparation and thereafter. Improved mechanical and mucoadhesive properties, enhanced in vitro release (7.5- to 9-fold increases in RRT300 min) and transcorneal permeation (5.4- to 8.86-fold increases in Papp) of curcumin was achieved by selected in-situ gelling inserts compared to a control curcumin suspension. The developed inserts demonstrated acceptable ocular tolerability, enhanced corneal permeability, and sustained release of curcumin along with retention of insert formulation F7 on the ocular surface for at least two-hours. This insert provides a viable alternative to conventional eye drop formulations of curcumin.