WO2009084069A2

WO2009084069A2 - Ocular solution with organic lycopene

Info

Publication number: WO2009084069A2
Application number: PCT/IT2008/000793
Authority: WO
Inventors: Leonardo Rescio
Original assignee: Lio Farmaceutici Srl
Priority date: 2008-01-02
Filing date: 2008-12-23
Publication date: 2009-07-09
Also published as: ITMI20080003A1; WO2009084069A4; WO2009084069A3

Abstract

Topical ocular solution comprising carotenoids, liposomes, plant lipids/cerasomes, phospholipids and viscosifying agents.

Description

Ocular solution with organic lycopene

DESCRIPTION

The present invention has as subject pharmaceutical compounds useful as eyewash and/or tear substitute comprising carotenoids such as natural lycopene and/or organic lycopene, lutein, zeaxanthine, astaxanthine, plant and synthetic lipids, phospholipids and linear and/or cross-linked hyaluronic acid and/or its salts or other viscosifying agents (for example carboxymethylcellulose, carbomer, and the like). Each of the aforesaid active ingredients can be used in formulation in free form or encapsulated in liposomes and/or cerasomes. The compositions of the invention are also useful both as per se active ingredients (for the treatment of retinal degenerations, like the diabetic retinal degeneration or AMD - Age-related macular degeneration), and as cicatrizants and/or carriers for other active ingredients in ophthalmology (for example antibiotics or cortisones or NSAIDs - Non-steroidal anti-inflammatory drugs). The technical problem resolved by the present invention is the creation of a tear substitute and/or eyewash which, in addition to the typical characteristics of the tear substitutes consisting of hydrating, lubricating and moistening capacity/effect, has further characteristics linked to the anti-oxidant activity of the carotenoids and the specific UVA/UVB radiation absorption activity of organic lycopene. The abovementioned characteristics are useful for the treatment of eye diseases. Dry eye syndrome, for example, is an eye disease characterised by the alteration of the natural lachrymal film, with serious discomfort and annoyance by the subject affected with such disorder. There are multiple causes of this disease, in particular phenomena tied to aging, environmental and atmospheric factors, use of contact lenses, autoimmune pathologies, trigeminal paralysis, oncological diseases, systemic pharmacological therapies, eye surgery operations (for example, various laser therapies or cornea transplants, palpebral operations or operations on the nerve ending level). Dry eye syndrome is currently treated systemically or topically. Systemic treatments are known at the state of the art comprising, for example, oral compositions based on unsaturated fatty acids (US7029712) or cysteine (WO02055068). For the topical treatments, tear substitutes are used in the form of eyewash or gel based on detergent, lubricating and possibility disinfecting compounds. Nevertheless, these products only act on the symptomatological level, and sometimes the preservatives contained therein tend to worsen the condition rather than resolve it. Treatments are also known at the state of the art which use glucocorticoids, like rimexolone (EPl 575597; US2006069075) and other anti-inflammatory agents (U.S. 6.506.412) for the treatment of possible inflammatory processes underlying the dry eye syndrome. Antibiotics are also used, for example tricyclic macrolide compounds (WO0066122) or peptides like duramycin (US2006035811). The present invention regards topical compositions comprising the association of carotenoids (organic lycopene) with phospholipids and/or plant or synthetic lipids with a viscoelastic agent, in particular as a tear substitute. This combination of substances has shown to be particularly effective in the topical treatment of the dry eye syndrome and of the retinal degenerations, such as for example diabetic retinopathy or AMD (Age-related macular degeneration). The compositions of the invention are also useful as carriers or as preservatives for other active ingredients. Said compositions have activities favouring the cicatrising or tissue regeneration processes. In particular, the composition of the tear substitute containing organic lycopene, subject of the present invention, is also capable of protecting the eye from dangerous UVAAJVB radiations. Examples of carotenoids comprise lycopene, lutein, zeaxanthine, astaxanthine, which can be used on their own or mixed with each other, each in percentages by weight generally in the range of 0.001 - 1%, preferably 0.01 - 0.5%. The plant lipids, such as for example olive oil and/or almond oil, are present in the compositions of the invention in percentages by weight generally in the range of 0.001 - 5%, preferably 0.001 - 4%. Said lipids can also be of synthetic origin. The phospholipids which can be employed according to the invention comprise soy lecithin or egg lecithin, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, polar lipid complexes (for example glycosyl ceramides and digalactosyl glycerides, etc.), various plant seed extracts and/or their mixtures in all proportions. The percentages by weight of said phospholipids or phospholipid mixtures or various lipid mixtures in the compositions of the invention vary from 0.001 to 10%. Cross-linked and non-cross-linked hyaluronic acids with different techniques are available on the market and are described for example in WO 2003/089476, EP 161887, GB 2151244, DE 3434082, EP 265116, EP 1313772. The compositions of the invention contain linear and/or cross-linked hyaluronic acid and/or its salts at a concentration in the range of 0.001% - 10% by weight, depending on the molecular weight, variable from 200 kDalton to 30 MDalton: a greater molecular weight corresponds with a smaller concentration, and vice versa. The compositions of the present invention can moreover contain linear and/or cross- linked hyaluronic acid and/or its salts, saturated or unsaturated fatty acids, antioxidant agents (Vitamin A, Vitamin E, Vitamin C, Resveratrol etc.), honey/royal jelly, antibiotics, antiinflammatory agents, cortisones and other active and/or proactive ingredients, Aloe vera extracts. The compositions of the present invention can may also contain or not a buffer solution. Said buffer solution, where existing, can be citrate, phosphate, borate or other. The present invention also has as subject the use of carotenoids (for example lycopene, lutein, zeaxanthine and/or astaxanthine), free or encapsulated in liposomes/cerasomes, in association with phospholipids and/or plant or synthetic lipids with linear and/or cross-linked hyaluronic acid and/or its salts, for the preparation of medications with cicatrizant/tissue repair activity in ophthalmology. In addition, the association of the invention can be used as a carrier and preservative for active ingredients of ophthalmic interest, for example beta-blocking (timolol, carteolol, etc.), prostaglandin, glucocorticoids, antibiotics, membrane stabilisers, metals, plant extracts (in particular Aloe vera, Ginkgo biloba). The compositions of the invention can be formulated according to well-known conventional methods, such as those described in "Remington's Pharmaceutical Handbook" Mack Publishing Co., N. Y., USA, using excipients, diluents, viscosifiers, isotonic agents and similar substances acceptable for their final use. In particular, viscoelastic substances will be advantageously used, such as sodium hyaluronate, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyacrylic acids (Carbopol), and beta-glucan. Examples of suitable formulations comprise eyewashes, sterile eye drops, gel, foams and ointments. Several composition examples are reported below: EXAMPLE l

Ingredients: %

Lycopene 0.2

Cerasomes 0.2 Lutein, Zeaxanthine, Astaxanthine < 0.2

Sodium hyaluronate 0.2

Citric acid 0.14

Sodium citrate 1.26

Sodium chloride 0.9 Sodium hydroxy de IN q.s to pH 6- 6.5

WFI bidistilled water q.s. to 100

EXAMPLE 2 Ingredients: %

Lycopene 0.5

Cerasomes 0.5

Lutein, Zeaxanthine, Astaxanthine 0.3

Plant lipids (olive oil and/or almond oil) 2 Phosphatidylcholine (50%)-Phosphatidylserine (50%) 5

Phospholipids 2

Cross-linked sodium hyaluronate, MW 2.0MDalton <7

Lactated Ringer's Solution (F.U.) 1

Vitamin A 0.1 Vitamin E 0.1

WFI bidistilled water q.s. to 100

EXAMPLE 3 Ingredients: %

Lycopene 0.3

Cerasomes 0.3

Resveratrol 0.1

Cross-linked sodium hyaluronate, MW 2.0 MDalton <5 Phosphatidylcholine (50%)-Phosphatidylserine (50%) 10

Lactated Ringer's Solution (F.U.) 1

Vitamin E 0.1

Plant lipids (olive oil and/or almond oil) 2

WFI bidistilled water q.s. to 100

EXAMPLE 4

Ingredients: %

Lutein and/or Zeaxanthine 0.5

Plant lipids (olive oil and/or almond oil) 2 Vitamin E 0.1 Cross-linked and/or linear hyaluronic acid and/or its salts <5

Phosphatidylcholine (50%)-Phosphatidylserine (50%) 10

Lactated Ringer's Solution (F.U.) 1

WFI bidistilled water q.s. to 100 EXAMPLE 5

Ingredients: %

Lutein and/or Zeaxanthine 0.5 Plant lipids (olive oil and/or almond oil) 2

Vitamin E 0.1

Hydroxypropylmethylcellulose (Hypromellose-HPMC) <5

Phosphatidylcholine (50%)-Phosphatidylserine (50%) 5

Lactated Ringer's Solution (F.U.) 1 WFI bidistilled water q.s. to 100

EXAMPLE 6

Ingredients: %

Lutein and/or Zeaxanthine 0.5 Plant lipids (olive oil and/or almond oil) 2

Resveratrol 0.1

Hydroxypropylmethylcellulose (Hypromellose-HPMC) <5

Phosphatidylcholine (50%)-Phosphatidylserine (50%) 5

Lactated Ringer's Solution (F.U.) 1 WFI bidistilled water q.s. to 100

EXAMPLE 7

Ingredients: %

Lycopene 0.5 Cerasomes 0.5

Resveratrol 0.1

Cross-linked sodium hyaluronate, MW 2.0MDalton <5

Lutein, Zeaxanthine, Astaxanthine 0.5 Phosphatidylcholine (50%)-Phosphatidylserine (50%) 3

Plant lipids (olive oil and/or almond oil) 4

Cross-linked and/or linear hyaluronic acid

MW 2.5 MDalton < 10

Disodium phosphate dodecahydrate 4 Sodium dihydrogen phosphate dihydrate 2

WFI bidistilled water q.s. to 100

EXAMPLE 8

Ingredients: %

Organic Lycopene 0.5

Cerasomes 0.5

Plant lipids (olive oil and/or almond oil) 4

Cross-linked and/or linear hyaluronic acid

MW 2.5 MDalton <10

Disodium phosphate dodecahydrate 4 Sodium dihydrogen phosphate dihydrate 2

Sodium chloride 0.7

WFI bidistilled water q.s. to 100

EXAMPLE 9

Ingredients: %

Organic Lycopene 0.5

Cerasomes 0.5

Lutein, Zeaxanthine, Astaxanthine 0.3

Plant lipids (olive oil and/or almond oil) 2

Phosphatidylcholine (50%)-Phosphatidylserine (50%) 5

Phospholipids 2

Cross-linked sodium hyaluronate,

MW 2.0 MDalton <7

Lactated Ringer's Solution (F.U.) 1

Vitamin A 0.1

Vitamin E 0.1

WFI bidistilled water q.s. to 100

EXAMPLE 10

Ingredients: %

Organic Lycopene 0.3

Cerasomes 0.3

Resveratrol 0.1 Cross-linked and/or linear sodium hyaluronate,

MW 2.0 MDalton <5

Phosphatidylcholine (50%)-Phosphatidylserine (50%) 10

Lactated Ringer's Solution (F.U.) 1

Vitamin E 0.1

Plant lipids (olive oil and/or almond oil) 2 WFI bidistilled water q.s. to 100

Claims

1) Topical ocular solutions comprising antioxidant agents such as carotenoids and liposomes/cerasomes, plant lipids and viscosifying agents. 2) Solutions according to claim 1, wherein the carotenoids comprise organic lycopene, lutein, zeaxanthine, astaxanthine or their mixtures. 3) Solutions according to claim 1 or 2, wherein the carotenoids are present in concentrations in the range of 0.01% - 0.5%. 4) Solutions according to claim 2 or 3, characterised in that they protect from UVA/UVB radiations.

5) Solutions according to one of the preceding claims, characterised in that it contains linear and/or cross-linked hyaluronic acid and/or its salts as moistening, lubricating as well as viscosifying agent.

6) Solutions according to claim 5, wherein the hyaluronic acid is present in concentrations in the range of 0.001% - 10% by weight.

7) Solutions according to claim 5 or 6, wherein the hyaluronic acid has a molecular weight from 200 kDalton to 30

MDalton.

8) Solutions according to one of the claims 1 - 4, containing viscoelastic substances such as polyvinyl alcohol and derivatives, polyvinylpyrrolidone and derivatives, hydroxypropylmethylcellulose and derivatives, carboxymethylcellulose and its derivatives, polyacrylic acids, xanthan and its derivatives, beta glucan and its derivatives, on their own or mixed with hyaluronic acid or its salts. 9) Solutions according to one of the preceding claims, wherein the plant lipids are present in concentrations in the range of 0.001% - 4%.

10) Solutions according to one of the preceding- claims, also comprising other antioxidant agents selected from among Vitamin A, Vitamin E, Vitamin C, Resveratrol and/or honey/royal jelly and/or antibiotics and/or anti-inflammatory agents and/or cortisones and/or other active and/or proactive ingredients and/or extracts of Aloe vera.

1 1) Solutions according to one of the preceding claims, characterised by the presence of a buffer solution.

12) Solutions according to one of the preceding claims, wherein said buffer solution is citrate, phosphate or borate.

13) Solutions according to one of the preceding claims, characterised by being used as tear substitute, in the treatment of Age-related Macular Degeneration, diabetic and hypertensive retinopathy, cornea repairing/cicatrising processes, degenerative processes of the eye surface and as carriers, stabilisers and preservatives for active ingredients.