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Process for the preparation of sterile ophthalmic aqueous fluticasone propionate form a nanocrystals suspensions

a technology of fluticasone and nanocrystals, which is applied in the field of preparation of sterile topical ophthalmic nanosuspensions, can solve the problems of loss of stabilizing effect, difficult de-agglomeration of nanocrystals, and difficult storage, so as to improve the preservation of multi-dose ophthalmic compositions, stable nanosuspensions, and easy adaptability to large-scale preparations

Pending Publication Date: 2022-08-04
NICOX OPHTHALMICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]Complexes of boric acid with polyhydroxyl compounds (borate-polyol complexes) are well known and it is generally known the use of borate-polyol complexes in ophthalmic composition to enhance antimicrobial activity.
[0021]WO 2010 / 148190 discloses borate-polyol complexes including two different polyols to improve preservation of multi-dose ophthalmic compositions.

Problems solved by technology

When the nanocrystals of Fluticasone propionate are directly suspended and de-agglomerated in a final vehicle that contains the pre-formed boric acid / glycerol complex the stabilizing effect is lost and the de-agglomeration of the nanocrystals is more difficult to achieve and to maintain during the storage.

Method used

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  • Process for the preparation of sterile ophthalmic aqueous fluticasone propionate form a nanocrystals suspensions
  • Process for the preparation of sterile ophthalmic aqueous fluticasone propionate form a nanocrystals suspensions
  • Process for the preparation of sterile ophthalmic aqueous fluticasone propionate form a nanocrystals suspensions

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0124]Preparation of Nanocrystals of Fluticasone Propionate Form A

[0125]Preparation of Phase I Solution

[0126]In a 2 L process vessel, 106.26 g polysorbate 80 (Tween 80), 963.34 g polypropylene glycol 400 (PPG 400), 324.10 g polyethylene glycol 400 (PEG 400), were added at room temperature and stirred together until all components were dissolved, then 6.3 g fluticasone propionate polymorph 1 was added into the solution and stirred until a clear solution was obtained. The obtained solution was filtered using a 0.8 / 0.2 μm Polyethersulfone (PES) filter and kept refrigerated at 2-8° C. until use.

[0127]Preparation of Phase II Solution

[0128]In an 8 L process vessel an initial quantity of about 5276 g of purified water was added and stirred with an over-head mixer so that a vortex was generated.

[0129]6.01 g polyethylene glycol 40 stearate (PEG-40 stearate), 5.98 g benzalkonium chloride (solution 10%), and 24.02 g methyl cellulose 15 cP were added and stirred till methyl cellulose was comple...

example 2

[0147]Preparation of a Sterile Topical Ophthalmic Aqueous Nanosuspension of Fluticasone Propionate Form A

TABLE 1Fluticasone propionate nanosuspension compositionIngredientsAmount (% w / w)Fluticasone propionate Form A nanocrystals0.10Methylcellulose 4000 cP0.50Polysorbate 800.2Edetate disodium, dihydrate0.10Boric acid1.0Glycerin0.9Benzalkonium chloride0.01Sodium chloride0.055Water for injectionq.s. to 100%pH7.3-7.5

[0148]Step 1) Preparation of Vehicle 1 (Vehicle without Glycerin)

[0149]In a 20 L process vessel, 17600 g water for injection were heated at 80° C., 100.0 g methylcellulose 4000 cP were slowly added and the mixture is stirred until methylcellulose was dissolved.

[0150]The solution was cooled at 40° C., 200.0 g boric acid was added and the pH was adjusted at 7.4 with sodium hydroxide (1N).

[0151]The following excipients were added in the specific following order: 20.0 g edetate disodium dihydrate, 11.0 g sodium chloride, 4.0 g benzalkonium chloride (solution 50%), 40.0 g polysor...

example 3

[0188]Evaluation of the Stability of the Nanosuspension of Example 2

[0189]The nanosuspension composition prepared in example 2 was subjected to storage stability testing by storing the nanosuspension at three different temperatures and humidity conditions (5° C., 25° C. / 40% RH; 40° C. / 25% RH) The resuspendability of the nanosuspension, the content of fluticasone propionate, the particle size distribution and the content of benzalkonium chloride were assessed at 1 month and 3-month time-points.

[0190]The results reported in tables 2 and 3 show that the nanosuspension was physically and chemically stable upon manufacture and storage. No change in physical appearance of the nanosuspension upon storage was noticed. The nanosuspension did not show any sign of chemical degradation as the chemical assay of fluticasone propionate was well within the limit of 90%-110% of the label claim upon storage. The related substances and total impurities remained within the specified limits of not more ...

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Abstract

The present invention relates to an improved process of manufacturing sterile topical ophthalmic aqueous nanosuspensions of nanocrystals of fluticasone propionate Form A. The sterile topical ophthalmic nanosuspensions are useful 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.

Description

FIELD OF THE INVENTION[0001]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.[0002]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[0003]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...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/569A61K9/10A61K9/00A61K47/38A61K47/26A61K47/18A61K47/02A61K47/10A61P27/04
CPCA61K31/569A61K9/10A61K9/0048A61K47/38A61P27/04A61K47/183A61K47/02A61K47/10A61K47/186A61K47/26A61K31/56A61P27/02A61P29/00B82Y5/00C07J31/006A61P27/00A61K9/14C07B2200/13A61K9/08A61K31/567
Inventor BUKOWSKI, JEAN-MICHELNADKARNI, AKSHAYBOYER, JOSÉ L.DUQUESROIX-CHAKROUN, BRIGITTENAVRATIL, TOMAS
Owner NICOX OPHTHALMICS
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