Preclinical characterization and clinical evaluation of tacrolimus eye drops

Luaces-Rodríguez, Andrea; Touriño-Peralba, Rosario; Alonso-Rodriguez, I; García-Otero, Xurxo; González‐Barcia, Miguel; Rodríguez‐Ares, María Teresa; Martínez-Pérez, Laura; Aguiar, Pablo; Gómez-Lado, Noemí; Silva‐Rodríguez, Jesús; Herranz, Míchel; Ruibal-Morell, Alvaro; Lamas, María Jesús; Otero-Espinar, Francisco J.; Fernández‐Ferreiro, Anxo

doi:10.1016/j.ejps.2018.04.038

Cited by 18 publications

(22 citation statements)

References 59 publications

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“…These observations are in accordance with the PET data described by Luaces-Rodriguez et al in the case of tacrolimus eye drops [ 39 ]. According to the literature, increasing fluid viscosity increases the residence time to some extent by delaying the tear action [ 26 ].…”

Section: Resultssupporting

confidence: 93%

Biopharmaceutical Assessment of Dexamethasone Acetate-Based Hydrogels Combining Hydroxypropyl Cyclodextrins and Polysaccharides for Ocular Delivery

et al. 2020

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We previously developed two optimized formulations of dexamethasone acetate (DXMa) hydrogels by means of special cubic mixture designs for topical ocular administration. These gels were elaborated with hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) and commercial hydrogels in order to enhance DXMa water solubility and finally DXMa’s ocular bioavailability and transcorneal penetration. The main objective of this study was to characterize them and to evaluate in vitro, ex vivo, and in vivo their safety, biopermanence, and transcorneal permeation. Gels A and B are Newtonian fluids and display a viscosity of 13.2 mPa.s and 18.6 mPa.s, respectively, which increases their ocular retention, according to the in vivo biopermanence study by PET/CT. These hydrogels could act as corneal absorption promoters as they allow a higher transcorneal permeation of DXMa through porcine excised cornea, compared to DEXAFREE® and MAXIDEX®. Cytotoxicity assays showed no cytotoxic effects on human primary corneal epithelial cells (HCE). Furthermore, Gel B is clearly safe for the eye, but the effect of Gel A on the human eye cannot be predicted. Both gels were also stable 12 months at 25 °C after sterilization by filtration. These results demonstrate that the developed formulations present a high potential for the topical ocular administration of dexamethasone acetate.

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Section: Resultssupporting

confidence: 93%

Biopharmaceutical Assessment of Dexamethasone Acetate-Based Hydrogels Combining Hydroxypropyl Cyclodextrins and Polysaccharides for Ocular Delivery

et al. 2020

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“…A newly published paper reported the results of a pilot clinical usage of a formulation composed of 0.03% Tacrolimus in 1.4% PVA, Sodium chloride, Sodium phosphate dibasic, Sodium phosphate monobasic, Benzalkonium chloride, Edetate disodium and Purified water on 8 patients (16 eyes) and they observed no adverse effects. 28 There is low and limited evidence in literature about Tacrolimus eye drop toxicity topic, and as described above, the available formulated forms have different vehicles but all studies on ocular formulations of Tacrolimus indicated almost the same pattern and revealed no significant toxicity when compared to the control groups. The results obtained from our study also followed the same pattern.…”

Section: Discussionmentioning

confidence: 99%

Preliminary In Vivo Safety Evaluation of a Tacrolimus Eye Drop Formulation Using Hydroxypropyl Beta Cyclodextrin After Ocular Administration in NZW Rabbits

Mahmoudi¹,

Malaekeh‐Nikouei²,

Hanafi‐Bojd³

et al. 2020

OPTH

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Aim: Tacrolimus is an immunosuppressive drug with higher potency compared to cyclosporine A (as a useful immunosuppressant). We prepared an ophthalmic solution formulation of Tacrolimus using hydroxypropyl beta cyclodextrin (HP-ßCD). In the present study, safety of this formulation was investigated in rabbits. Materials and Methods: Formulation containing HP-ßCD, Tacrolimus, Polyvinyl alcohol (PVA) and Benzalkonium Chloride in PBS 7.4 was prepared. Tacrolimus concentration in ophthalmic preparation was 0.05% w/v. Ten male New Zealand white rabbits were housed in clean separated cages. One drop of Tacrolimus prepared formulation and a placebo formulation were applied every 12 hrs in the right and left eyes respectively, for 28 days. Results: This new aqueous formulation of Tacrolimus could improve Tacrolimus solubility about 42 times. Clinical examinations on the 1st, 3rd, 7th, 14th and 28th days of study showed transient redness and conjunctivitis in some cases of both control and intervention groups that was not persistent. At the end of the study, there were no statistical differences between the two groups in corneal epithelial defect, redness or pathological evaluations. Conclusion: The results of this study suggest that eye drop formulation of CD-Tacrolimus is safe in preliminary evaluations and can be useful for further studies.

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“…Some in vivo methods assess transcorneal permeation by radiolabelling and imaging by gamma scintigraphy [124] or positron emission tomography [215]. The successful use of tracers added to the formulation relies upon the properties of the vehicle remaining unchanged and, therefore, behaving in a manner that is identical to that in the absence of the tracer so that the results obtained are a genuine reflection of the residence time of the dosage form.…”

Section: In Vivo Testsmentioning

confidence: 99%

Recent Advances in the Design of Topical Ophthalmic Delivery Systems in the Treatment of Ocular Surface Inflammation and Their Biopharmaceutical Evaluation

et al. 2020

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Ocular inflammation is one of the most common symptom of eye disorders and diseases. The therapeutic management of this inflammation must be rapid and effective in order to avoid deleterious effects for the eye and the vision. Steroidal (SAID) and non-steroidal (NSAID) anti-inflammatory drugs and immunosuppressive agents have been shown to be effective in treating inflammation of the ocular surface of the eye by topical administration. However, it is well established that the anatomical and physiological ocular barriers are limiting factors for drug penetration. In addition, such drugs are generally characterized by a very low aqueous solubility, resulting in low bioavailability as only 1% to 5% of the applied drug permeates the cornea. The present review gives an updated insight on the conventional formulations used in the treatment of ocular inflammation, i.e., ointments, eye drops, solutions, suspensions, gels, and emulsions, based on the commercial products available on the US, European, and French markets. Additionally, sophisticated formulations and innovative ocular drug delivery systems will be discussed. Promising results are presented with micro- and nanoparticulated systems, or combined strategies with polymers and colloidal systems, which offer a synergy in bioavailability and sustained release. Finally, different tools allowing the physical characterization of all these delivery systems, as well as in vitro, ex vivo, and in vivo evaluations, will be considered with regards to the safety, the tolerance, and the efficiency of the drug products.

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Preclinical characterization and clinical evaluation of tacrolimus eye drops

Cited by 18 publications

References 59 publications

Biopharmaceutical Assessment of Dexamethasone Acetate-Based Hydrogels Combining Hydroxypropyl Cyclodextrins and Polysaccharides for Ocular Delivery

Biopharmaceutical Assessment of Dexamethasone Acetate-Based Hydrogels Combining Hydroxypropyl Cyclodextrins and Polysaccharides for Ocular Delivery

<p>Preliminary I<em>n</em> V<em>ivo</em> Safety Evaluation of a Tacrolimus Eye Drop Formulation Using Hydroxypropyl Beta Cyclodextrin After Ocular Administration in NZW Rabbits</p>

Recent Advances in the Design of Topical Ophthalmic Delivery Systems in the Treatment of Ocular Surface Inflammation and Their Biopharmaceutical Evaluation

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