US-12622881-B2 - Water-soluble topical ophthalmic preparation containing lutein and production method thereof

US12622881B2US 12622881 B2US12622881 B2US 12622881B2US-12622881-B2

Abstract

A method for the production of a topical ophthalmic preparation useful as a tear substitute and agent for the treatment of the computer vision syndrome and the related product are disclosed. In addition to the water-soluble ingredients typical of aqueous eye drops or gels, the preparation also contains a stable micellar solution (or microemulsion) of lutein with vitamin E TPGS.

Inventors

Nevio VONA
Walter QUATTROCCHI
GIUSEPPE DEL VECCHIO

Assignees

OMISAN FARMACEUTICI S.R.L.

Dates

Publication Date: 20260512
Application Date: 20220322
Priority Date: 20210322

Claims (12)

1 . A process for the production of a water-soluble ophthalmic topical preparation containing lutein, said process comprising, in sequence, the following operations: Step 1: a) introducing a predetermined amount of deionized water and, optionally, the components of a buffer system and, also optionally, a predetermined amount of an ophthalmic viscosifying agent into a first stirred vessel, waiting for the complete solubilization of the optional ingredients; Step 2: a) in a second stirred vessel, heating a predetermined amount of vitamin E tocopherol polyethylene glycol succinate (TPGS) up to a temperature of 80-90° C., and waiting for complete melting thereof; b) bringing the vitamin E TPGS to a temperature of 90-170° C. and adding a predetermined amount of lutein, while continuing stirring until complete dissolution and formation of a homogeneous orange oily solution, consisting exclusively of vitamin E TPGS and lutein; Step 3: a) heating the water or the aqueous solution obtained from operation a) of Step 1 to a temperature of 80-90° C. and adding an aliquot thereof equal to about 10% by volume of the final product, gradually, to said second vessel, while keeping it under stirring; b) once the addition is complete, increasing the stirring speed while maintaining the temperature in the 90-170° C. range until a completely clear and optically homogeneous orange liquid is obtained; and Step 4: a) adding the solution of Step 3 to the remaining water or aqueous solution obtained from operation a) of Step 1; b) after verifying that the temperature has fallen down to or below, 30° C., adding to the stirred vessel other optional water-soluble ingredients of the topical ophthalmic preparation being produced, one at a time and in predetermined quantities, said optional water-soluble components comprising one or more viscosifying agents and/or mucoadhesives, waiting for the complete solubilization thereof; c) sterilizing the product thus obtained.
2 . The production process according to claim 1 , wherein said topical ophthalmic preparation is in liquid form, and wherein the composition further comprises a buffer system in step 1a.
3 . The production process according to claim 1 , wherein, in said operation a) of Step 1, a predetermined amount of cross-linked hyaluronic acid (HA-CK) is also introduced into said first stirred vessel.
4 . The production process according to claim 1 , wherein said one or more viscosifying and/or mucoadhesive agents of said operation b) of Step 4 comprise hyaluronic acid or a salt thereof (HA), or carboxymethylcellulose (CMC) or cross-linked carboxymethylcellulose (CMC-CK).
5 . The production process according to claim 1 , wherein said sterilization operation c) of Step 4 is carried out by filtering the product obtained through a 0.2 μm filter.
6 . The production process according to claim 1 , wherein the topical ophthalmic preparation is in the form of a gel; wherein step 4b further comprises a predetermined amount of a gelling agent added to the stirred vessel through a sieve, while continually stirring to obtain a lump free dispersion, and followed by neutralizing the dispersion with a neutralizing agent.
7 . The production process according to claim 6 , wherein said sterilization operation c) of Step 4 is carried out by subjecting the obtained product to autoclaving or to a treatment with gamma rays.
8 . A topical ophthalmic preparation consisting of a stable micellar solution (microemulsion) of vitamin E TPGS and lutein, suspended in an aqueous phase comprising viscosifying and/or mucoadhesive agents or gelling agents, together with other ophthalmologically acceptable excipients, said preparation being obtainable as described in claim 1 .
9 . The topical ophthalmic preparation according to claim 8 , wherein said viscosifying and/or mucoadhesive agents are selected from the group consisting of: hyaluronic acid or a salt thereof (HA), cross-linked hyaluronic acid (HA-CK), carboxymethylcellulose (CMC), cross-linked carboxymethylcellulose ((CMC)-CK) and their mixtures.
10 . The topical ophthalmic preparation according to claim 8 , wherein said gelling agents are based on a carboxyvinyl polymer.
11 . The production process according to claim 2 , wherein the components of a buffer system are one of borate, citrate and phosphate buffer.
12 . The production process according to claim 6 , wherein said gelling agent is a carboxyvinyl polymer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a 35 U.S.C. § 371 National Phase of PCT Application No. PCT/IT2022/050064, filed Mar. 22, 2022, which claims priority to Italian Application No. 102021000006839, filed Mar. 22, 2021, the disclosures of which are hereby incorporated by reference herein. FIELD OF THE INVENTION The present invention relates to a water-soluble topical ophthalmic preparation containing lutein and the production method thereof. More particularly, the invention relates to a specific process for the production of a tear substitute which, in addition to the necessary viscosifying and mucomimetic agents and the usual additives typical of aqueous eye drops, such as buffers, osmoprotective or isotonizing agents, chelating and possibly antimicrobial agents, also contains a fat-soluble active ingredient with a high antioxidant and photoprotective power, lutein, in combination with a well-known emulsifier, vitamin E TPGS. A specific sequential preparative method makes it possible to obtain a stable micellar solution (or microemulsion) suitable for topical ophthalmic administration. BACKGROUND OF THE INVENTION The organ of sight, which has the function of capturing the luminous radiations coming from the external world to transform them into nerve impulses, used for perceptive purposes such as vision and reflexes, is separated from the external environment by the tear film, a layer of liquid in turn composed of several layers. The tear film is continuously and uniformly distributed on the ocular surface by the closure of the eyelids and has a crucial function in maintaining the homeostasis of the ocular surface. It allows adequate lubrication of the corneal epithelium by reducing friction with the eyelids, allows the transport and diffusion of vital molecules (oxygen, carbon dioxide, ions, mucins, lipids) for the survival of the epithelia and cornea. It also possesses a marked antibacterial activity, thanks to the presence of some enzymes and, finally, it guarantees the exchange and keeps the ocular surface clean, removing impurities coming from the environment, metabolic waste and desquamated cells. From the outside towards the inside, the layers of the tear film are as follows: 1) a thin superficial lipid layer, produced by the meibomian glands, which has the function of delaying the evaporation of the underlying aqueous layer, preventing the escape of tears from the eyelid margins and maintaining hydration during the hours of sleep;2) an intermediate aqueous layer, containing different molecules (electrolytes, proteins, amino acids, organic acids) with enzymatic and antibacterial functions, which provide for the protection, nutrition and replacement of the epithelium, as well as reducing the friction of blinking and washing the ocular surface of the numerous impurities that are deposited there;3) an innermost mucous layer, consisting of mucin, with a marked hydrophilicity, the presence of which allows the aqueous layer to spread over the otherwise highly hydrophobic corneal epithelium. The stability of the tear film is therefore the result of the balance of different components, the alteration of which can lead to the onset of lacrimal dysfunction syndrome, also known as dry eye syndrome, and other ophthalmic diseases. The aqueous layer of the tear film is constantly subjected to evaporation, which is continuously compensated by the tear secretion. When this compensatory secretion for some reason is reduced or insufficient, the symptoms of dry eye disease appear, consisting of a dehydration that involves continuous ocular discomfort, with foreign body sensation in the eye, itching, burning, difficulty opening your eyes, desire to wash or rub your eyes, discomfort when looking at the light, eyestrain during the day. Reddened and less luminous eyes are almost always a sign of a bad state of hydration of the ocular surface. Dry eye due to reduced tear production is distinguished more precisely into two main subclasses: dry eye associated with Sjögren's syndrome (SSDE), a chronic inflammatory disease of an autoimmune nature, and dry eye not caused by Sjögren's syndrome, which collects the cases of lacrimal dysfunction in which the systemic autoimmune aspects characteristic of the SSDE have been excluded. Also some ocular surface diseases can change the amount and composition of tear fluid. The most obvious case is that of blepharitis, in which the inflammation of the eyelid creates alterations in the production of the secretion of the meibomian glands, with consequent alteration of the tear film. Even the incorrect use of contact lenses, of any type, worn for too many hours during the day, can cause an alteration of the tear film. Another problem, which appeared in more recent times, which shares some of the symptoms associated with dry eye syndrome, is caused by the massive use of smartphones and computers, and of all screens that emit light radiation that interact with the differ