Tacrolimus concentration was determined for each sample using an HPLC system (Agilent 1260 series; Agilent Technologies, Santa Clara, CA, USA) equipped with a Diode Array Detector HS, a solvent delivery quaternary pump system, 400 bar maximum pressure and an autosampler. We can let your veterinarian know that you are interested in our compounded Tacrolimus. The aim of this work was to develop a mucoadhesive, non-toxic and stable topical ophthalmic formulation that can be safely prepared in hospital pharmacy departments. The simulated test was performed on formulations having been stored for eight months (M8) at 5 C, and the storage temperature was maintained at 5 C during the test, except for drop emission. Behrens-Baumann, W.; Theuring, S.; Brewitt, H. The Effect of Topical Cyclosporin A on the Rabbit Cornea. (a) Maximum breaking strength (N) and (b) bioadhesion work (mJ) obtained for each formulation using bovine cornea as a substrate. Pharmaceutical Codex [58] has established the margins of the expiration period of the formulations as being once the concentration of active ingredient is reduced by 10% concerning the initial concentration. In addition to conducting a MilliQ water solubility study, it was studied whether the tacrolimus solubility varied in different media in which the final tacrolimus eye drops could be formulated. Wan, Q.; Tang, J.; Han, Y.; Wang, D.; Ye, H. Therapeutic Effect of 0.1% Tacrolimus Eye Drops in the Tarsal Form of Vernal Keratoconjunctivitis. The purpose of this assay was to know the required tacrolimus solubilization time in the eye drops so that when the formulation has to be replicated in an HPD, the drug will not be removed when performing the sterilizing filtration, ensuring quality, final product efficacy and patient safety. Chennell, P.; Delaborde, L.; Wasiak, M.; Jouannet, M.; Feschet-Chassot, E.; Chiambaretta, F.; Sautou, V. Stability of an Ophthalmic Micellar Formulation of Cyclosporine A in Unopened Multidose Eyedroppers and in Simulated Use Conditions. Formulations also showed good ophthalmic properties in terms of pH, osmolality and safety. Nonetheless, both eye drops preserved in refrigeration (4 2 C) were stable beyond the 3-month period; specifically, the initial concentration of tacrolimus previously fell below 90% in the TLI 40 formulation compared to the TBS 40 formulation. Veterinarians typically use tacrolimus in dogs and cats as either a topical skin ointment or an ophthalmic eye drop. ; investigation, X.G.-O. The formulations were labeled as TBS 20 (20% (w/v) HPCD and 0.01% (w/v) of tacrolimus in BSS), TBS 40 (40% (w/v) HPCD and 0.02% (w/v) of tacrolimus in BSS), TLI 20 (20% (w/v) HPCD and 0.01% (w/v) of tacrolimus in Liquifilm) and TLI 40 (40% (w/v) HPCD and 0.02% (w/v) of tacrolimus in Liquifilm) (see Table 1). Formulations were successfully prepared by an inclusion complex/dissolution technique. Pharmacology and Therapeutics for Dentistry. Corneal bioadhesion was used to quantitatively determine the interaction between the formulation and the corneal bovine surface. WebResults: TAC-HPCD eye drops demonstrated to reduce ocular inflammation, expression of IL-6, TNF-, MIP-1 and leukocyte infiltration in aqueous humor. These surface tension values can be given by HPCD, which shows values of 54.857.5 mN/m in solution, as it was previously mentioned by Saokham et al. Han K., Woghiren O.E., Priefer R. Surface tension examination of various liquid oral, nasal, and ophthalmic dosage forms. The https:// ensures that you are connecting to the Each formulation was tested in triplicate. Hayes, R.; Ahmed, A.; Edge, T.; Zhang, H. CoreShell Particles: Preparation, Fundamentals and Applications in High Performance Liquid Chromatography. See also Warning section. All other chemicals and reagents were of the highest purity grade commercially available. http://creativecommons.org/licenses/by/4.0/, https://www.clinicaltrials.gov/ct2/show/NCT03865888webpage, https://www.ema.europa.eu/en/cyclodextrins, https://www.vidal.fr/medicaments/indocollyre-0-1-collyre-sol-en-recipient-unidose-8613.html, https://www.scienceopen.com/document?vid=76f1d8c7-413c-40f2-aa7f-227482d5d1ad, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q2-r1-validation-analytical-procedures-text-and-methodology, https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4bd4d59c-eb3b-4a5e-9eb7-ae95b0a92bea&type=display, https://cima.aemps.es/cima/pdfs/es/ft/60226/FT_60226.pdf, https://patentimages.storage.googleapis.com/b3/43/bc/d55228f30c3e35/US7441468.pdf, /paper/1-Subgroup-3-.-Eye-Irritation-Eskes-Bessou/6dc8084ae36aec2ab4ca59586e230776bafd8f5d, http://www.arvo.org/About_ARVO/Policies/Statement_for_the_Use_of_Animals_in_Ophthalmic_and_Visual_Research/, https://patentimages.storage.googleapis.com/6e/1b/c3/0718a34b45e98c/US5591426.pdf. The selective saturation was applied during 2 s at a specific frequency of the 1H spectrum, covering a region of the spectrum of 125 Hz around the chosen frequency (i.e., 0.17 ppm in a 750 spectrometer). 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). In: Dowd F.J., Johnson B.S., Mariotti A.J., editors. Use sunscreen and wear clothing and eyewear that protects you from the WebTacrolimus is also sometimes used to treat fistulizing Crohn's disease (a condition in which the body attacks the lining of the digestive tract, causing pain, diarrhea, weight loss, fever, and the formation of abnormal tunnels connecting the digestive tract to other organs or the skin). Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The IVIS was determined by the following Equation (2): The hens egg test on the chorioallantoic membrane (HETCAM) assay is one of the new organotypic models that allows the identification of irritative reactions, and it has become the international standard assay for acute eye irritation and corrosion (OECD TG 405, 2002; EC B.5). Pharmacokinetics parameters (K, t1/2, AUC0, mean residence time (MRT) and % remaining formulation at 75 min) of the tacrolimus eye drops obtained by the fitting of the percentage formulation remaining on ocular surface. Therapeutic Effect of 0.03% Tacrolimus Ointment for Ocular Graft versus Host Disease and Vernal Keratoconjunctivitis. Tacrolimus aqueous solubility in the absence of cyclodextrins was 4 0.67 g/mL, and K1:1 and K1:2 values were 143.1 10.3 and 2.1 0.6 M-1, respectively. Based on this, both formulations (TBS 40 and TLI 40) were aseptically prepared under laminar air flow. Furthermore, microbiological control growth is a test to take into account the quality control of the prepared formulations since it ensures the sterility of the preparations and, therefore, the conditions of asepsis in the production process. pH and osmolality monitoring were performed to observe the presence of any changes. A solubility study was carried out by adding an excess amount of the tacrolimus powder to MilliQ aqueous solutions containing increasing concentrations of HPCD (from 0 to 400 mg/mL). NMR experiments were conducted at two different temperature conditions, 278 and 298 K, on a Bruker NEO 17.6 T spectrometer (proton resonance 750 MHz) (Billerica, MA, USA), equipped with a 1H/13C/15N triple resonance PA-TXI probe with a deuterium lock channel and a shielded Pulse Field Gradient (PFG) z-gradient. Tacrolimus Ultrapure water MilliQ (Millipore Iberica; Madrid, Spain) was used throughout the whole work. However, the United States Pharmacopoeia allows this interval for a tacrolimus compounded oral solution [, This work also used the Arrhenius equation to be able to estimate the impact of various temperatures on tacrolimus degradation. Spectra were processed and analyzed using Mestrenova v14.0 software (Mestrelab Research S.L., Santiago de Compostela, Spain, 2019). Use of topical FK506 in a corneal graft rejection model in Lewis rats. Zhai, J.; Gu, J.; Yuan, J.; Chen, J. Tacrolimus in the Treatment of Ocular Diseases. Just click ! Applicability of the du Nouy apparatus. Nevertheless, statistically significant differences were observed ( < 0.05) between 20% (w/v) HPCD formulations and 40% (w/v) HPCD formulations as well as between 40% (w/v) HPCD formulations and REF for times beyond 30 min post-administration. The analytical method was validated according to International Conference on Harmonization (ICH) guideline recommendations [44]. Plotting Ln(C), with C in mol/L, as a function of time (seconds), as presented in, With Ea = 1413.624 J/mol and A = 745005719.4 s, According to Equation (7), the time to fall to 90% of initial tacrolimus concentration at 30 C would be. K1:1 and K1:2 values were calculated by non-linear regression using GraphPad Prism 8 v.8.2.1 software. Clinical Case Notes. These results support the idea that these new formulations could be used without generating adverse effects in the ocular surface, compared to the control formulation (REF) [15] where, despite showing a pH value within the physiological range (pH 4 to 8) [68], the osmolality values (1220.5 mOsm/kg) were four times higher than the limit value for topical ophthalmic administration. Adding HPCD to formulations, apart from increasing the solubility and stability of tacrolimus, also gave a more viscous and stickier characteristic to the solution. The pathogenesis of uveitis is often caused by an autoimmune response. ; Santo, R.M. This research received no external funding. Ophthalmic Solution for Artificial Tears 1997. A sterile ophthalmic solution of 0.3 mg/mL tacrolimus was prepared in triplicate under aseptic conditions by diluting tacrolimus in eye drops. Fan, Z.; Zhang, L. One- and Two-Stage Arrhenius Models for Pharmaceutical Shelf Life Prediction. ; Batista, A.D.S. 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. Thus, NMR studies were performed in order to study the part of the drug and cyclodextrin structure involved in the complex formation. This content is intended for counseling purposes only. Higuchi T., Connors K., Connors S. Phase Solubility Techniques. 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. The mean volume of a drop was determined to be 25.0 L and 25.7 L, respectively, for the 1 mg/mL and 0.2 mg/mL formulation, with the density being of 0.9815 and 0.98805. Wang Y., Wang C., Fu S., Liu Q., Dou D., Lv H., Fan M., Guo G., Luo F., Qian Z. Then, corneas were kept in touch with the formulation for 30 s, and just after returning to the starting point at a 1 mm/s speed, work (mJ) was measured. Tacrolimus Luechtefeld T., Maertens A., Russo D.P., Rovida C., Zhu H., Hartung T. Analysis of Draize eye irritation testing and its prediction by mining publicly available 2008-2014 REACH data. Study Design Go to 2,4-Di-tert-butylphenol possessed a quasi-identical relative retention time (1.069, relative to tacrolimus) and UV spectrum. those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). mol, First, the degradation rate k for each storage temperature was calculated after verification that the concentration (C) decreased following a first order reaction (i.e., C = C, It is then possible to extrapolate, for different temperatures, the k value to determine a stability time such as the time (, The stability of the tested tacrolimus formulations was evaluated using the following physicochemical parameters: visual aspect of the solution, turbidity and micelle size, viscosity, pH and osmolality, tacrolimus concentration and a research of BPs. Tacrolimus eye drops elicited a statistically significant difference in the mean total clinical scores and IOP over the course of treatment (P < 0.001). The tacrolimus solubility was tested in two different vehicles besides MilliQ water, these being BSS and Liquifilm. 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. The eggs were automatically rotated in an automatic rotational incubator every 2 h until the eighth day, where rotation was stopped, and the eggs were kept in the axial position during 24 h for the proper placement of the chorioallantoic membrane (CAM). Different formulations are proposed in the present work as new pharmacological alternatives, specifically intended for topical ophthalmic administration for uveitis treatment. Do not save this mixture for later use. WebConclusions Tacrolimus eye drops are highly effective in treating refractory allergic conjunctivitis with proliferative lesions and/or corneal involvement, and may reduce or replace topical steroid use. Similarly, opacity and permeability data were corrected for background or control values prior to further statistical determinations being estimated. International Conference of Harmonization (ICH) Quality Guidelines: Guidelines for Stability Q1A to Q1f. Chast, F.; Lemare, F.; Legeais, J.-M.; Batista, R.; Bardin, C.; Renard, G. Prparation dun Collyre de Ciclosporine 2%. The main reason for this weak interaction between the drug and cyclodextrin may be the high molecular weight and the complex molecular structure of tacrolimus that hampered an adequate adaptation to the cyclodextrin cavity. Zhai J., Gu J., Yuan A.P.J., Chen P.J. Prajapati, M.; Eiriksson, F.F. Please select your state below. FOIA This method was carried out using slaughterhouse materials (fresh bovine corneas), allowing the animal replacement compliance and avoiding the use of laboratory animals. Long-term outcomes of 0.1% tacrolimus eye drops in eyes with Based on this background, the novelty of this work relies on the obtention of a consistent preclinical base for a new safe, stable and bioadhesive tacrolimus eye drop designed for appropriate preparation by HPDs. Uveitis is a recurrent and common ophthalmic disease that has an idiopathic etiology, caused by a complication of an infection or associated with a systemic disease (infectious or autoimmune disorder) [3,9]. On topical application, the TAC concentrations in rabbit cornea and conjunctiva one hour after Corneal transparency was measured in transmittance values by UVVis spectrophotometry (from 200 to 800 nm), allowing the light to pass through the corneas, from the source to the receiver of the spectrophotometer (Cary 60 UV-Vis, Agilent Technologies; Santa Clara, CA, USA). Eye Drops Lee Y.J., Kim S.W., Seo K.Y. Taormina, D.; Abdallah, H.Y. Signals of HPCD are indicated in spectrum (a). 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). Impact of Uveitis on Quality of Life: A Prospective Study from a Tertiary Referral Rheumatology-Ophthalmology Collaborative Uveitis Center in Italy. Oh, J.Y. The presence of any abnormal macroscopic particles in the formulations was not considered acceptable. [54], with minor modifications. However, the reference formulation (REF) showed lower surface tension values than the others, being associated to the presence of ethanol in its composition. 405 HERON DRIVE SUITE 200 SWEDESBORO, NJ 08085-1749 | 2004-2023 WEDGEWOOD PHARMACY, ALL RIGHTS RESERVED. For instance, tacrolimus can cause kidney damage.