US-12622872-B2 - Process for the preparation of sterile ophthalmic aqueous fluticasone propionate form a nanocrystals suspensions

US12622872B2US 12622872 B2US12622872 B2US 12622872B2US-12622872-B2

Abstract

A process of manufacturing sterile topical ophthalmic aqueous nanosuspensions of nanocrystals of fluticasone propionate Form A. The sterile topical ophthalmic nanosuspensions may be used in the treatment of eye inflammation conditions such as blepharitis, posterior blepharitis, Meibomian gland dysfunction and dry eye through topical administration of said nanosuspensions to eyelids, eyelashes and eyelid margin.

Inventors

Jean-Michel BUKOWSKI
Akshay NADKARNI
José L. Boyer
Brigitte DUQUESROIX-CHAKROUN
Tomas Navratil

Assignees

NICOX OPHTHALMICS, INC.

Dates

Publication Date: 20260512
Application Date: 20220627

Claims (12)

1 . An ophthalmic aqueous nanosuspension administrable topically onto eyelids, eyelashes or eyelid margin consisting of: (a) 0.1% w/w fluticasone propionate Form A nanocrystals and a vehicle consisting of: (b) 0.50% w/w methylcellulose 4000 cp; (c) 0.2% w/w polysorbate 80; (d) 0.1% w/w edetate disodium dihydrate; (e) 1.0% w/w boric acid; (f) 0.9% w/w glycerol; (g) 0.01% w/w benzalkonium chloride; (h) 0.055% w/w sodium chloride; (i) hydrochloric acid 1N and/or sodium hydroxide 1N as adjusting agents in an amount sufficient to pH 7.3-7.5; and (j) water q.s. to 100% w/w, wherein said nanocrystals of fluticasone propionate Form A have a mean particle size from 100 nm to 1000 nm and a X-ray powder diffraction pattern comprising peaks at about 7.8, 15.7, 20.8, 23.7, 24.5, and 32.5 degrees 2⊖, further comprising peaks at about 9.9, 13.0, 14.6, 16.0, 16.9, 18.1, and 34.3 degrees 2⊖, and wherein the nanocrystals are nanoplates having a [001] crystallographic axis normal to a surfaces that define a thickness of the nanoplates, wherein said ophthalmic aqueous nanosuspension contains a boric acid/glycerol complex.
2 . The ophthalmic aqueous nanosuspension according to claim 1 , wherein the boric acid/glycerol complex is formed by adding the glycerol to a de-agglomerated slurry containing the fluticasone propionate Form A nanocrystals suspended in a vehicle that contains the boric acid but does not contain the glycerol.
3 . A method of treating dry eye disease comprising topically applying an effective amount of the ophthalmic aqueous nanosuspension according to claim 1 to eyelids, eyelashes and eyelid margin of a subject in need thereof.
4 . A method of reducing the symptoms and/or clinical signs associated with dry eye disease comprising topically applying an effective amount of the ophthalmic aqueous nanosuspension according to claim 1 to eyelids, eyelashes and eyelid margin of a subject in need thereof.
5 . The method according to claim 3 , wherein the method comprises applying an effective amount of the ophthalmic aqueous nanosuspension at least once a day for at least two weeks to a subject in need thereof.
6 . The method according to claim 4 , wherein the method comprises applying an effective amount of the ophthalmic aqueous nanosuspension at least once a day for at least two weeks to a subject in need thereof.
7 . The ophthalmic aqueous nanosuspension according to claim 1 and a swab or sponge to apply said aqueous nanosuspension to eyelids, eyelashes or eyelid margin.
8 . A method of treating dry eye disease comprising topically applying an effective amount of the ophthalmic aqueous nanosuspension according to claim 2 to eyelids, eyelashes and eyelid margin of a subject in need thereof.
9 . A method of reducing the symptoms and/or clinical signs associated with dry eye disease comprising topically applying an effective amount of the ophthalmic aqueous nanosuspension according to claim 2 to eyelids, eyelashes and eyelid margin of a subject in need thereof.
10 . The method according to claim 8 , wherein the method comprises applying an effective amount of the ophthalmic aqueous nanosuspension at least once a day for at least two weeks to a subject in need thereof.
11 . The method according to claim 9 , wherein the method comprises applying an effective amount of the ophthalmic aqueous nanosuspension at least once a day for at least two weeks to a subject in need thereof.
12 . The ophthalmic aqueous nanosuspension according to claim 2 and a swab or sponge to apply said aqueous nanosuspension to eyelids, eyelashes or eyelid margin.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of Ser. No. 16/934,807, filed Jul. 21, 2020, which claims priority to U.S. Provisional Application No. 61/161,006, filed Mar. 17, 2009 and U.S. Provisional Application No. 62/877,599, filed Jul. 23, 2019, the contents of which are each hereby incorporated by reference in their entireties. FIELD OF THE INVENTION The present invention relates to a process for the preparation of sterile topical ophthalmic nanosuspensions containing nanocrystals of fluticasone propionate Form A in an aqueous vehicle. This process is readily adaptable to preparation for large-scale production and leads to sterile homogeneous aqueous nanosuspensions having a stable particle size distribution. The sterile topical ophthalmic aqueous nanosuspensions containing fluticasone propionate Form A nanocrystals are useful in the treatment of eye inflammation diseases or eye inflammatory conditions through topical administration of said nanosuspensions (or nanocrystals suspensions) to eyelids (e.g. upper and lower lids), eyelashes and eyelid margin. BACKGROUND OF THE INVENTION Nanocrystals of fluticasone propionate Form A are nanoplates having the [001] crystallographic axis substantially normal to the surfaces that define the thickness of the nanoplates. The fluticasone propionate Form A nanocrystals are prepared from a commercially available fluticasone propionate polymorph 1 by the anti-solvent sonocrystallization process disclosed in WO 2013/169647. WO 2013/169647 discloses the preparation of nanocrystals of a morphic form of fluticasone propionate (Form A), their purification and also the preparation of the aqueous suspensions containing said nanocrystals. Briefly, according to the continuous sonicating flow-through scale-up process disclosed by WO 2013/169647 (Example 11 and FIG. 38) the nanocrystals of fluticasone propionate are prepared using antisolvent crystallization under sonication followed by the thermal annealing of the nanosuspension; the generated nanocrystals are purified by continuous flow centrifugation, the vehicle of the nanosuspension is centrifuged out, the pellet is re-dispersed in the washing solution and the dispersion centrifuged again. This washing procedure is repeated several times to achieve the desired level of purification. The pellet is then dispersed into the final formulation composition to obtain the final product at required dose strength. However, WO 2013/169647 does not report any data related to the sterility tests of the nanosuspension. The applicant has found that the continuous sonicating flow-through process disclosed by WO 2013/169647 allows to prepare high amounts of fluticasone propionate Form A nanocrystals but it is not suitable for a large-scale preparation of sterile ophthalmic aqueous nanosuspensions because the dispersion of the purified nanocrystals (pellet) into the final aqueous vehicle (see FIG. 38) does not allow to produce a final product having the sterility requirements that must be met by pharmaceutical formulations for ocular delivery. Moreover, during the preparation of large-scale volumes of the nanosuspension it was found that, during the mixing of the purified nanocrystals with the final aqueous vehicle, the nanocrystals tended to form agglomerates that were difficult to be de-agglomerated therefore making difficulty to obtain homogeneous nanosuspensions. Moreover, even when some effective deaggregation and homogenous nanosuspensions were obtained extemporaneously, these nanosuspensions exhibited some propensity to reaggregate and to be unstable. As it is well known, nanoparticles have a high propensity to agglomerate due to their high surface energy that cause the formation of agglomerates during the preparation and storage of the nanosuspensions, Aggregation of the nanoparticles is not only a critical aspect during the manufacturing of the suspensions; agglomeration can cause a variety of issues, for example, inconsistent dosing and patient non-compliance. In particular, for nanosuspensions intended for application onto the eyelids, eyelashes and eyelid margin, agglomeration, may impact the tolerability in patients and potential safety. Several strategies to ensure proper physical stability of drug nanosuspensions are well known. For example, stabilizers are usually used, however, the selection of an appropriate stabilizer for a certain drug can be challenging. US 2018/0117064 discloses the preparation of aqueous suspensions containing nanoparticles of a glucocorticosteroid compound and a dispersion stabilizer. US 2018/0117064 discloses that the main function of the stabilizer is to wet the drug particles thoroughly to prevent Ostwald ripening and agglomeration of the nanosuspension and to form a physically stable formulation by providing asteric or an ionic barrier. Typical examples of stabilizers used in nanosuspensions are celluloses, poloxamer, polysorbates, lecithin, polyoleate and povidones. WO