Each formulation was tested in triplicate. Tacrolimus solubility with 20%, 30% and 40% (w/v) of HPCD in Balanced Salt Solution (BSS) and Liquifilm vehicles. Uveitis is a vision inflammatory disorder with a high prevalence in developing countries. All formulations showed no toxic effects (irritation score = 0) compared them with the positive control formulation (see Figure 12). Subsequently, 400 L of the supernatant was taken to measure the tacrolimus concentration by HPLC (Agilent 1260 series; Agilent Technologies, Santa Clara, CA, USA) with the method described above (see Section 2.1.1. 1Pharmacology, Pharmacy and Pharmaceutical Technology Department, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15705 Santiago de Compostela, Spain; se.csu.iar@aicrag.oxrux (X.G.-O. Corneal bioadhesion was used to quantitatively determine the interaction between the formulation and the corneal bovine surface. There are few reports on the use of cyclodextrins to improve the pharmaceutical characteristics of tacrolimus [37]. Bouattour, Y.; Chennell, P.; Wasiak, M.; Jouannet, M.; Sautou, V. Stability of an Ophthalmic Formulation of Polyhexamethylene Biguanide in Gamma-Sterilized and Ethylene Oxide Sterilized Low Density Polyethylene Multidose Eyedroppers. Interacts with grapefruit juice, numerous medications, and even some supplements. Ezquer-Garin, C.; Ferriols-Lisart, R.; Als-Almiana, M. Stability of Tacrolimus Ophthalmic Solution. Besides, additional goals were also pre-established such as ease of preparation, scalability from the laboratory scale to HPDs and patient comfort improvement. No peaks were seen when silicone parts were put into contact with only water. Validation study of alternatives to the Draize eye irritation test in Germany: Cytotoxicity testing and HET-CAM test with 136 industrial chemicals. It was observed that during the separation stage of the cornea from the formulation, a formulation film remained adhered to the cornea when the load cell was lifted. ; Dew, W.; Feinberg, M.; Lallier, M.; et al. Prajapati, M.; Eiriksson, F.F. Thus, the absence of microorganisms and suspended particles was in good agreement with the preparation of this type of topical ophthalmic formulations in HPDs, by a simple technique with non-strict equipment requirements. Lee, J.S. A Receptor for the Immuno-Suppressant FK506 Is a CisTrans Peptidyl-Prolyl Isomerase. Luaces-Rodrguez A., Tourio-Peralba R., Alonso-Rodrguez I., Garca-Otero X., Gonzlez-Barcia M., Rodrguez-Ares M.T., Martnez-Prez L., Aguiar P., Gmez-Lado N., Silva-Rodrguez J., et al. ; Galat, A.; Uehling, D.E. Badr, M.Y. WebCyclosporine eye drops may cause side effects. Nevertheless, no differences were found between TLI 20 and TLI 40, nor between TBS 20 and TBS 40. pH and osmolality determinations were carried out in order to ensure that the formulations show values within the ocular physiological range. The need to increase the solubility and stability of the drug becomes a task of extreme necessity. Expiration dates up to 1 year! ; Writingreview & editing: all authors. Available online: French Society of Clinical Pharmacy (SFPC) and Evaluation and Research Group on Protection in Controlled Atmospher (GERPAC). Dissolution time comparison among the different tacrolimus formulations. The animals were treated according to the ARVO statement for the use of animals in ophthalmic and vision research as well as the approved guidelines for laboratory animals [59,60]. Uno T., Yamaguchi T., Li X.K., Suzuki Y., Hashimoto H., Harada Y., Kimura T., Kazui T. The pharmacokinetics of water-in-oil-in-water-type multiple emulsion of a new tacrolimus formulation. Likewise, the fluorescein permeability test was further applied on the corneas previously treated with the tested formulations. The oligosaccharide 2-hydroxypropyl--cyclodextrin (HPCD) is a cyclic oligosaccharide formed by seven units of -1,4-linked glucose and a hydroxypropylated group, with a lipophilic central cavity and a hydrophilic outer surface. As presented in Figure 6, a proportional increase in the tacrolimus solubility was observed by increasing the amount of cyclodextrin included into the vehicle. ; Investigation: M.B., Y.L.B. and P.C. A quadratic model equation allows the estimation of both stability constants (K1:1 and K1:2). Prajapati et al. Afterward, 7.5 L of each tacrolimus formulation, previously radiolabeled with 18F-fluorodeoxyglucose (18F-FDG), was instilled into the conjunctival sac of both eyes using a micropipette. Purpose: Taking into account all of the obtained results, TLI 40 was proposed as the best candidate. As presented in Figure 7, 20% (w/v) HPCD formulations containing tacrolimus reached 100% solubilization in a 90-h period, while 40% (w/v) HPCD formulations containing tacrolimus showed different solubilization time, being quicker for the TLI 40 (72-h period, against the 90-h period for TBS 40). Tacrolimus concentrations used in clinical practice are very variable (0.005% to 0.1% range) [11,17,48,49]; it should be noted that the selection of the designated tacrolimus concentration has been carried out on the basis of previous experimental studies (see Section 2.1.3. This method was performed following the method established by Charles H. Cox, with minor modifications [51], in a Shimadzu texturometer (Kyoto, Japan). Currently, marketed treatments remain limited and reformulation is usually performed to obtain a tacrolimus eye drop as a therapeutic alternative in corticosteroid-refractory eye disease. Tacrolimus is one of a group of relatively new drugs used to treat dry eye in dogs and cats. ; Ko, J.H. The TLI 40 vehicle (Liquifilm) is composed of PVA; this polymer has a mechanism based on the interdiffusion of polymer chains across the bioadhesive interface that produces entanglements and physical bonds between the polymer and the substrate. The aim of this work was based on the design and development of different topical ophthalmic formulations containing tacrolimus as an alternative to the reformulated Prograf intravenous solution (REF). Positron Emission Tomography for the Development and Characterization of Corneal Permanence of Ophthalmic Pharmaceutical Formulations. Fresh corneas were mounted in Franz diffusion cells with the corneal epithelial surface facing upwards, dividing the two different chambers of the diffusion cell (donor and receptor). Direct and indirect resource use, healthcare costs and work force absence in patients with non-infectious intermediate, posterior or panuveitis. All formulations were kept under refrigeration conditions (4 2 C) to avoid degradation processes of the drug when they were prepared. Zeng W., Li Q., Wan T., Liu C., Pan W., Wu Z., Zhang G., Pan J., Qin M., Lin Y., et al. The intermolecular interaction between tacrolimus and HPCD in aqueous solution was studied by NMR in the tacrolimus/HPCD mixture prepared in D2O at a 200 mM HPCD concentration and tacrolimus saturation (0.2 mM). Eskes C., Bessou S., Bruner L., Curren R., Harbell J., Jones P., Kreiling R., Liebsch M., McNamee P., Pape W., et al. The combination of two different methods has been proposed in this work. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Veterinarians typically use tacrolimus in dogs and cats as either a topical skin ointment or an ophthalmic eye drop. Four different ophthalmic formulations were prepared based on the tacrolimus/hydroxypropyl--cyclodextrin (HPCD) inclusion complexes formation. FOIA ; Silva, F.Q. This content is intended for counseling purposes only. Tacrolimus (Topical Route) Print Sections Description and Brand Names Before Using Proper Use Precautions Side Effects Products and services Proper Use Tell your doctor if any of these symptoms are severe or do not go away: burning, itching, stinging, redness, or pain of the eyes eyelid swelling eye discharge blurred vision or other vision changes feeling that something is in the eye headache Some side effects can be serious. ; Ptachcinski, R.J.; Todo, S.; Fung, J.J.; Starzl, T.E. Lamprecht A., Yamamoto H., Takeuchi H., Kawashima Y. To prevent the rats from scratching their eyes by removing the instilled formulations, an Elizabethan collar was placed between PET studies. ; Lee, J.-E. The results guaranteed that all tested formulations were also in the appropriate range for topical ophthalmic administration, ensuring suitability for an accurate tacrolimus ocular penetration. Hayes, R.; Ahmed, A.; Edge, T.; Zhang, H. CoreShell Particles: Preparation, Fundamentals and Applications in High Performance Liquid Chromatography. The radiotracer uptake over time was corrected by the radioisotope decay (18F half-life: 109.7 min). ; Nguyen-Huu, J.-J. The authors declare no conflict of interest. Cyclodextrin properties may also improve the mucoadhesive characteristics of the formulations, leading to a retention time increase on the ocular surface. Use sunscreen and wear clothing and eyewear that protects you from the The .gov means its official. Tacrolimus in the Treatment of Ocular Diseases. Refrigerated and accelerated samples were kept at room temperature for 20 minutes before quantification. Evaluation of Tacrolimus Sorption to PVC- and Non-PVC-Based Tubes in Administration Sets: Pump Method vs. Drip Method. The development of new ophthalmic topical vehicles for increasing drugs permanence on the ocular surface is important to improve drug bioavailability in the eye as well as the treatment adherence by patients [81]. No significant structural changes were observed in terms of corneal opacity and fluorescein permeability when comparing all formulations to the negative control solution (PBS) but were observed with regard to the positive control (ethanol) ( < 0.05). Joseph A., Raj D., Shanmuganathan V., Powell R.J., Dua H.S. The STDon and STDoff scans were measured in alternate scans and subtracted by the phase cycling, providing the subtracted STDoff-on spectra. Adding HPCD to formulations, apart from increasing the solubility and stability of tacrolimus, also gave a more viscous and stickier characteristic to the solution. Throughout the study, turbidity did not vary by more than 0.4 FNU when stored at 5 C and 1 FNU for the 25 C and 35 C storage temperature conditions for the 1 mg/mL concentration. On topical application, the TAC concentrations in rabbit cornea and conjunctiva one hour after tacrolimus 30g of 0.1% 1 tube of ointment at Safeway $236 $ 74.55 Save 68% BIN PCN Group Member ID 015995 GDC DR33 DEX950664 Tacrolimus is a macrolide with a high molecular weight (804.02 g/mol) isolated from Streptomyces tsukubaensis, with a great immunosuppressive activity (100 times more potent than cyclosporine A) [10,11] that inhibits T cell proliferation and suppresses the release of inflammatory cytokines; it can theoretically be used to reduce inflammatory activity in uveitis patients [3]. Impact of Uveitis on Quality of Life: A Prospective Study from a Tertiary Referral Rheumatology-Ophthalmology Collaborative Uveitis Center in Italy. In addition, the presence of benzalkonium chloride in Liquifilm could help to prevent microbial growth once the eye drops were opened. Study Design Go to those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). Spielmann H., Kalweit S., Liebsch M., Wirnsberger T., Gerner I., Bertram-Neis E., Krauser K., Kreiling R., Miltenburger H., Pape W., et al. The micelle size for a tacrolimus-free formulation was similar to that of the tacrolimus formulations. ; Luin, T.T. Pharmacokinetics of topically applied tacrolimus dissolved in Marinosolv, a novel aqueous eye drop formulation. Signals of HPCD are indicated in spectrum (a). Ophthalmic Solution for Artificial Tears 1997. A comparison of the cyclodextrin formulations with each other and between the reference one was made in order to assess the presence or absence of significant differences depending on their composition. pH, osmolality and surface tension results of tacrolimus/HPCD formulations. Based on this, they can be classified as follows: 00.9, no irritation; 14.9, slight irritation; 58.9, moderate irritation; and 921, severe irritation. Ex vivo bioadhesion and in vivo ocular permanence showed good mucoadhesive properties with higher ocular permanence compared to the reference pharmacy compounding used in clinical settings (t1/2 of 86.2 min for the eyedrop elaborated with 40% (w/v) HPCD and Liquifilm versus 46.3 min for the reference formulation). Statistical analysis: (a) one-way ANOVA followed by Tukeys multiple comparison test (* < 0.05 compared with TLI 20, TBS 40 and TLI 40 and ** < 0.05 compared with TLI 20, TBS 40 and TLI 40); (b) one-way ANOVA followed by Tukeys multiple comparison test (* < 0.05 compared with TLI 20 and ** < 0.05 compared with TLI 20 and TBS 40). [(accessed on 21 January 2021)]; Daz-Tom V.D., Garca-Otero X., Blanco-Fernndez G., Fernndez-Ferreiro A., Otero-Espinar F.J., Varela-Fernndez R. In Vitro and in Vivo Ophthalmic Bioadhesion and Ocular Safety Characterization of Cyclodextrin Based Solution. BSS is an isotonic salt solution for use in irrigating eye tissues, with pH 7.5 and a 300 mOsm/kg osmolality [46]. Fiege, H.; Voges, H.-W.; Hamamoto, T.; Umemura, S.; Iwata, T.; Miki, H.; Fujita, Y.; Buysch, H.-J. International Conference of Harmonization (ICH) Quality Guidelines: Guidelines for Stability Q1A to Q1f. Tacrolimus formulations mucoadhesion was measured following a method designed and developed by our research group using a Shimadzu texturometer [52]. Phase solubility diagrams, Nuclear Magnetic Resonance (NMR) and molecular modeling studies showed the formation of 1:1 and 1:2 tacrolimus/HPCD inclusion complexes, being possible to obtain a 0.02% (w/v) tacrolimus concentration by using 40% (w/v) HPCD aqueous solutions. Therefore, the optimal storage condition for tacrolimus topical ophthalmic formulations was at 4 C. Nevertheless, this type of treatment has shown different disadvantages, including high osmolality and patient discomfort due to the eye drop composition. Cox C.H. The HPCD used in this work (Kleptose HPB) was a mixture of hydroxypropylated--CDs with a substitution mean degree of 0.65 (0.580.68; a mean of 4.2 hydroxypropyl groups per cyclodextrin molecule). Components responsible for the surface tension of human tears. Eye drops stored at oven temperature (40 2 C) were not stable in the first 7 days of the study, observing a rapid tacrolimus degradation process. Efficacy and safety of low-dose topical tacrolimus in vernal keratoconjunctivitis. Chast, F.; Lemare, F.; Legeais, J.-M.; Batista, R.; Bardin, C.; Renard, G. Prparation dun Collyre de Ciclosporine 2%. There are several types of -cyclodextrin (CD) derivatives, although most of them have not been authorized or there are not enough preclinical studies to support their use at the topical ophthalmic level [36]. Mix tacrolimus oral granules with water right before you take them. Tacrolimus solubilization with HPCD results), the HPCD and tacrolimus concentrations were chosen. ; Santo, R.M. The analysis was performed under an isocratic method. The stability study was only carried out with the formulations containing the greatest amount of drugs due to the fact that all the formulations have the same composition, the formulations with 40% (w/v) HPCD being the most representative, as they have a greater amount of the components with activity and based on the clinical common usability and the drug concentration similarity at present. All tacrolimus eyedrops were tested on the eggs CAM as well as two controls, NaCl as a negative control (C-) and NaOH as a positive control (C+). ; Giuffrida, R.; Pereira, C.S.G. The Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Visual Research. Baranowski P., Karolewicz B., Gajda M., Pluta J. Ophthalmic Drug Dosage Forms: Characterisation and Research Methods. Baudouin, C.; Labb, A.; Liang, H.; Pauly, A.; Brignole-Baudouin, F. Preservatives in Eyedrops: The Good, the Bad and the Ugly. Tacrolimus , another immunosuppressant, has been used in treatment of immune and inflammatory ocular diseases.This study describes a prospective controlled Higuchi T., Connors K., Connors S. Phase Solubility Techniques. 8600 Rockville Pike Use of them does not imply any affiliation with or endorsement by them. Tukeys multiple comparison test was also applied, and no statistically significant differences were found between the tacrolimus/HPCD formulations, but significant differences were observed between the reference formulation (REF) and the prepared formulations ( < 0.05). Three STDon-off spectra were measured at 278 and 298 K under otherwise identical conditions. The preparation of ophthalmic tacrolimus formulations is limited by its poor water solubility (112 g/mL) [27,28] due to the hydrolytic mechanism [29]. Careers, Unable to load your collection due to an error. This drug has been used in different ocular diseases including corneal graft rejection [12,13,14], vernal keratoconjunctivitis (VKC) [15,16,17], dry eye [11,18], uveitis [5,19,20], scleritis [21,22] or graft-versus-host disease [23,24,25], among others. Comparison of the Efficacy of 0.03% Tacrolimus Eye Drops Diluted in Olive Oil and Linseed Oil for the Treatment of Keratoconjunctivitis Sicca in Dogs. In this way, it was determined that eye drops kept in refrigeration condition have an available period of at least 3 months. This affection can lead to other types of complications, including cataract, increased intraocular pressure (IOP), macular edema (ME) or glaucoma, compromising visual loss [3,4,5]. HPCD dissolution was carried out in triplicate (10 mL per formulation), and the amount of tacrolimus powder was added once all the cyclodextrin was dissolved. 2,4-Di-tert-butylphenol possessed a quasi-identical relative retention time (1.069, relative to tacrolimus) and UV spectrum. The complexation between drugs and cyclodextrin affects many drugs physicochemical properties, including their chemical stability and aqueous solubility [39]. and transmitted securely. [, This information justified the choice of pH for the buffer used in our formulation, ranging from about 5.5 to 6 for the 0.2 and 1 mg/mL formulations, respectively. Stability studies of pharmaceutical compounds are essential to ensure drug efficacy [79,80] as well as to know if degradation products can cause toxic side effects and other undesired effects [27]. ); se.sagres@aicrag.olednom.anitsirc (C.M.-G.), 4Clinical Neurosciences Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain, 5Nuclear Magnetic Resonance Unit, Research Infrastructures Area, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; se.csu@nitram.leunam, 6Paraquasil Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain, 7Physiology DepartmentCIMUS, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; se.cdu@zedumreb.zeravla.airam, 8Ophthalmology Department, Clinical University Hospital Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain; se.csu@zelaznog.ocsicnarf, 9Department of Surgery and Medical-Surgical Specialties and CIMUS, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain. Additionally, clinical studies have shown tacrolimus high effectivity compared to other immunosuppressants such as cyclosporine, at lower concentrations [26]. The squeezing force test evaluates the force needed to dispense a drop from 5-mL polypropylene eyedropper bottles that are commonly used in HPDs. The platinum du Nuy ring was washed with alcoholic KOH, rinsed in MilliQ water and flamed until red-hot before each measurement. In Figure 14, the permanence of the studied eye drops at different times can be seen more visually, with PET/CT images showing both coronal planes (rat eyes and nasolacrimal duct). Based on these statements, it would be interesting to design new topical ophthalmic formulations with the lowest possible toxic potential and better tolerability. All data were assessed through breaking strength (N) and bioadhesion work (mJ) measurements (Figure 9). Tacrolimus concentration, pH and osmolality stability of (a) TBS 40 and (b) TLI 40 stored under three different temperature conditions: in refrigeration (4 2 C), at room temperature (25 2 C) and at oven temperature (40 2 C) during a 4-month stability test. The mobile phase was water-acetonitrile (35:65 (v/v)) using a 1.5 mL.min1 flow rate. Several types of tacrolimus formulations such as niosomes [30], nanoemulsions [5], microspheres [31], nanocapsules [32], micelles [33], emulsions [34] or liposomes [35] have also been described by other authors. Formulations were successfully prepared by an inclusion complex/dissolution technique. Disclaimer/Publishers Note: The statements, opinions and data contained in all publications are solely Initial mean pH was of 5.97 2.05% and 5.56 5.03%, respectively, for the 1 mg/mL and 0.2 mg/mL tacrolimus formulations. Gao S., Sun J., Fu D., Zhao H., Lan M., Gao F. Preparation, characterization and pharmacokinetic studies of tacrolimus-dimethyl--cyclodextrin inclusion complex-loaded albumin nanoparticles. A two-way ANOVA was subsequently performed to compare all the media and assess the inclusion complexes formation. Harmonization of Strategies for the Validation of Quantitative Analytical Procedures: A SFSTP ProposalPart III. The vials containing these suspensions were then shaken in a VWR incubated mini-shaker (VWR International, Radnor, PA, USA) at 25 C and 250 rpm for 7 days until reaching an equilibrium. In this study, the PET/CT imaging technique was used to determine the residence times of the proposed tacrolimus topical ophthalmic formulations on the ocular surface, and they were compared with the tacrolimus eye drop (REF) elaborated by HPDs. No variation exceeding 10% of the mean concentration measured at M8 was found for the 1 mg/mL eye drops as seen in the. WebConclusions: Tacrolimus eye drops may be able to play an adjunctive therapeutic role in patients with severe corneal endothelial rejection refractory to conventional steroid treatment. The solubility measurements were carried out following the previous work of our research group, described by Anguiano-Igea et al. Eye Irritation. In addition, no macroscopic changes (e.g., color, turbidity and precipitation) were observed during the whole study period. A Lauda TD1 tensiometer (LAUDA Scientific GmbH, Lauda-Knigshofen, Germany) fitted with a platinum ring (2-cm diameter) was used to measure the surface tension of the tacrolimus formulations. Squeeze Force Measuring System. Ordering patient medications is easy. Harmonization of Strategies for the Validation of Quantitative Analytical Procedures: A SFSTP ProposalPart, I. Hubert, P.H. An in vitro irritation score (IVIS) can be calculated with the measurements of corneal opacity and permeability. WebResults: In the efficacy study, STT increased by 5 mm/min in 84.7%, 25.0%, 26.7% and 51.1% of eyes in categories 1, 2, 3 and 4 respectively after tacrolimus administration. MeSH terms Administration, Topical Adolescent Adult Aged The pathogenesis of uveitis is often caused by an autoimmune response. The authors declare no conflict of interest. The formulation signal on the eye surface is coded on a color scale: blue areas show low radioactive activity whereas red areas show high radioactive activity. A one-way ANOVA was applied to determine the required force to dispense a drop of each formulation, and statistically significant differences were observed ( < 0.05). ; resources, M.G.-B, J.B.-M. and P.A. [(accessed on 17 November 2020)]; Q2 (R1) Validation of Analytical Procedures: Text and Methodology.