WO2012090170A1

WO2012090170A1 - Products for ophtalmic use

Info

Publication number: WO2012090170A1
Application number: PCT/IB2011/055992
Authority: WO
Inventors: Davide Sacchetti
Original assignee: ENABLE INNOVATIONS SpA
Current assignee: ENABLE INNOVATIONS SpA
Priority date: 2010-12-30
Filing date: 2011-12-28
Publication date: 2012-07-05
Anticipated expiration: 2013-06-30
Also published as: ITMO20100369A1

Abstract

The present invention relates to a composition comprising an extract of vegetable origin and the use of such a composition in the ophthalmic field.

Description

PRODUCTS FOR OPHTHALMIC USE

The present invention relates to a composition comprising an extract of vegetable origin, the use of such composition in the ophthalmic field, a single-use package comprising such composition.

Perilla is an annual herbaceous plant belonging to the Laminaceae family, typical of southeast Asia and generally used for human consumption and as as a medicinal plant in traditional medicine, especially Chinese, Korean and Japanese traditional medicine (and is known as "Shiso"). The leaves of Perilla Frutescens L. are known for their detoxifying, antitussive, antibiotic and antipyretic properties, moreover they are used in traditional medicine for the treatment of intestinal disorders and allergies (reference: Journal of Agricultural and Food Chemistry, 2005, 53, 8141-8147 -"DETERMINATION OF PHENOLIC COMPOUNDS IN PERILLA FRUTESCENS L. BY CAPILLARY ELECTROPHORESIS WITH ELECTROCHEMICAL DETECTION').

In particular, the Perilla L. genus in turn includes four different species of Perilla, of which the most commonly cultivated is Perilla frutescens L. Britton, the other species being Perilla hirtella Nakai; Perilla seyatoensis G. Honda; Perilla citriodora Nakai. Other species of Perilla such as Perilla aguta Benth., Perilla albiflora Odash., Perilla ocimoides L. are ascribed to the Perilla frutescens species (reference: Acta Poloniae Pharmaceutica - Drug Research, Vol. 66 No. 4 pp. 409-413, 2009 ISSN 0001-6837- Polish Pharmaceutical Society - 'PRELIMINARY ANALYSIS ON ESSENTIAL OIL COMPOSITION OF PERILLA L. CULTIVATED IN LITHUANIA ") and is used in traditional medicine, especially Chinese, Korean and Japanese traditional medicine.

The leaves, but also the seeds, of this plant are particularly rich in polyphenolic substances including rosmarinic acid, luteolin and other derivatives thereof, caffeic acid, apigenin and other derivatives thereof, ferulic acid (reference: Journal of Agricultural and Food Chemistry, 2005, 53, 8141-8147 -'DETERMINATION OF PHENOLIC COMPOUNDS IN PERILLA FRUTESCENS L. BY CAPILLARY ELECTROPHORESIS WITH ELECTROCHEMICAL DETECTION"). Moreover, in the leaves there are several carotenoids including chlorophyll a, chlorophyll b, beta- carotene and lutein (reference: Food and Chemical Toxicology, 48, 2010, 264-270 - "DETERMINATION OF TOXIC PERILLA KETONE, SECONDARY PLANT METABOLITES AND ANTIOXIDATIVE CAPACITY IN FIVE PERILLA FRUTESCENS L. VARIETIES"). In particular, the red- green colored leaves of the frutescens variety of Per ilia Frutescens L. harvested in China in the Guangdong region have been found to be particularly rich in polyphenols (reference: Molecules 2009, 14, 133-140; DOI: 10.3390/molecules 14010133 - "ANTIOXIDANT ACTIVITIES OF POLYPHENOLS EXTRACTED FROM Perilla FRUTESCENS VARIETIES".

The seeds of the plants of the Perilla genus are instead rich in lipids, the overwhelming majority of which are triacylglycerols while a small proportion is made up of phytosterols. The fatty acids that make up the triacylglycerols are represented mostly by alpha-linolenic and linoleic acid, i.e. polyunsaturated fatty acids belonging to the omega-3 and omega-6 family, by oleic acid, monounsaturated, and other saturated fatty acids such as palmitic and stearic acid (Reference: Songklanakarin J. Ski. Technol. , 2006, 28 (Suppl. l): \l-2 \ - " VARIATION OF LIPID AND FATTY ACID COMPOSITIONS IN THAI Perilla SEEDS GROWN AT DIFFERENT LOCATIONS".

In the ophthalmic field, compositions are known for the topical administration of a substance or of combinations of substances used for the treatment or attenuation of a disorder in humans, by exerting a pharmacological, metabolic or immunological action (in which case they are referred to as medicines), or by way of a mechanical action, i.e. not a pharmacological or metabolic or immunological action (in which case they are referred to as medical devices). Such compositions can be in the form of solutions, both as an aqueous solution with low or medium viscosity, and as a gel with medium to high viscosity.

Surprisingly, it has been found that it is possible to obtain a formulation that is antioxidant, antiallergic and lenitive of painful sensations in the eye caused by different factors, environmental and otherwise, using a solution of an extract of Perilla, optionally with conveniently selected components.

In one aspect, the present invention relates to a composition with high biocompatibility which is suitable for ophthalmic administration comprising an extract of Perilla.

The composition of the invention enables the administration of active ingredients of natural origin in a formulation that is stable and can be standardized with regard to the polyphenol content.

In particular, it has been found that the ophthalmic use of solutions of extracts of plants of the Perilla frutescens L. genus containing fatty acids and polyphenols makes it possible to combine lenitive properties, owing to the refreshing action and to the action of the dilution of environmental contaminants including allergens, and antioxidant properties for contrasting free radicals.

Preferably, in the composition of the invention the extract is produced starting from leaves and seeds of at least one plant of the Perilla frutescens L. genus and in particular from Perilla ocymoides L. originating from China and Japan (Reference: EPO Data Sheet of Perilla 2.5% dry hydroalcoholic extract, rev. 2 of 10-09-2009).

Preferably, in the composition of the invention, the Perilla extract is in the form of a dry hydroalcoholic extract comprising 2.5%, by weight of the total weight of the extract, of polyphenols derived from Perilla and wherein the Perilla extract is present in a percentage of from 0.1 % to 5% by weight of the total weight of the composition. The extract, characterized by an Extract/Drug (E/D) ratio of 1 : 10, is obtained by way of extraction of the seeds and leaves of the plant in a 70:30 ethanol/water mixture. The extract is stabilized with maltodextrin from maize which are present in a maximum percentage of 30%. The extract does not contain preservative or antioxidant substances. The titer of total polyphenols is determined by way of Folin- Ciocalteu spectrophotometric analysis (Reference: EPO DATA SHEET FOR PERILLA 2.5% DRY HYDROALCOHOLIC EXTRACT, rev. 2 of 10-09- 2009).

The presence of polyphenols of Perilla frutescens L. is the source of the antioxidant and antiallergic properties of the plant and of its extracts. In particular, the antioxidant action appears to work both by way of a contrasting action against free radicals (such as for example superoxide radicals), chelation of metals and acting as a reducing agent (primary antioxidant mechanism), and also by way of a metabolic interaction with induction or inhibition of specific cellular enzymes (secondary antioxidant mechanism) (Reference: Plant Food for Human Nutrition 2009, 10.1007/sl l 130-009-0152-x - "EFFECT OF SPINACIA OLERACEAE L. AND PERILLA FRUTESCENS L. ON ANTIOXIDANTS AND LIPID PEROXIDATION IN AN INTERVENTION STUDY IN HEALTHY INDIVIDUALS"; Journal of Medicinal Plants Research, Vol. 4(6), pp. 477- 483, 18 March 2010 - "ANTIOXIDANT AND ANTIPROLIFERATIVE ACTIVITIES OF METHANOLIC EXTRACTS OF Perilla FRUTESCENS"; Journal Agric. Food Chem. 1998, 46, 4545-4550 - "SUPEROXIDE SCA VENGING ACTIVITY OF ROSMARINIC ACID FROM Perilla FRUTESCENS BRITTON VAR. ACUTA F. VIRIDIS").

The antiallergic property, which renders the composition of the invention useful for contrasting, for example, allergic rhinoconjunctivitis, is also correlated with the composition of the extract of Perilla and specifically with the presence of rosmarinic acid, as well as other macromolecular compounds. The extract of Perilla in fact seems to be capable of influencing all three characteristic stages of type I allergic reactions, i.e. it seems to be capable of inhibiting the production of antigen- specific immunoglobulin E (IgE), of decreasing the release of histamine and other mediators of inflammation by the mast cells and hence the inflammatory response, such as for example the increase in vascular permeability and the contraction of the smooth muscles (Reference: Phytotherapy Research 2003, 17, 240-243 - "ANTI ALLERGIC EFFECT OF Perilla FRUTESCENS AND ITS ACTIVE CONSTITUENTS"). This leads to an improvement in allergic rhinitis, hay fever and hives. Pharmacological studies on Perilla do not show toxicity and no significant side effects are reported in clinical studies (Reference: Experimental Biology and Medicine, 2003 - "EXTRACT OF Perilla FRUTESCENS ENRICHED FOR ROSMARINIC ACID, A POLYPHENOLIC PHYTOCHEMICAL, INHIBITS SEASONAL ALLERGIC

RHINOCONJUNCTIVITIS IN HUMANS"). The extracts of Perilla moreover do not exhibit the secondary effects of synthetic antiallergic pharmaceuticals (antihistamines) which negatively affect quality of life, such as drowsiness, little ability to concentrate, contraindication of driving and dependency.

Preferably, the composition of the invention moreover comprises hyaluronic acid, in the form of sodium salt, polysaccharide polymer with high biocompatibility. This is in fact present in all body tissues and fluids in vertebrates, and in particular in the connective tissue. One of the parts of the body where the concentration of hyaluronic acid is highest is the vitreous body of the eye. Hyaluronic acid has a great capacity for hydration by retaining water molecules and in the hydrated state it exhibits a viscoelastic behavior that makes it an excellent lubricant (Reference: "Jo urnal of Internal Medicine 1997, 242, 27-33 "HYALURAN: ITS NATURE, DISTRIBUTION, FUNCTIONS AND TURNOVER"). Hyaluronic acid also has the property of making formulations more viscous, for the purpose of extending the time the formulation remains on the ocular surface (Reference: Clinical and Experimental Ophthalmology 1990, 225:510-512 - "PRECORNEAL RESIDENCE TIME IN HUMANS OF SODIUM HYALURONATE AS MEASURED BY GAMMA SCINTIGRAPHY'). For many years hyaluronic acid has also been known to be capable of modulating the healing of wounds without the formation of filamentous connective tissue and scars. The effect seems to be correlated to the presence of a high quantity of this macromolecule in the extracellular matrix at the site of the wound (Reference: Ann Surg. 1991 April; 213(4): 292-296 - STUDIES IN FETAL WOUND HEALING. V. A PROLONGED PRESENCE OF HYALURONIC ACID CHARACTERIZES FETAL WOUND FLUID).

Preferably, in the compositions of the invention the hyaluronic acid content is at least equal to 0.1% w/w and more preferably greater than 0.2% by weight of the total weight of the composition.

Preferably, the composition of the invention can be prepared in a form without preservatives, a characteristic that makes it possible to eliminate or in any case reduce to the minimum the possibility of allergic reaction and of interactions between the components of the composition. The preparation of a formulation without preservatives, both in terms of chemical properties and of microbiological properties (sterility), is made possible by the particular combination and choice of raw materials and of the manufacturing process. Specifically, the chemical stability of the special composition of the invention which contains Perilla depends on the chemical stability characteristics of the components and in particular on the chemical stabilization of the hydroalcoholic extract of Perilla by way of maltodextrins. The microbiological stability depends on the type of production process applied (a process under aseptic conditions) together with the use of a sterile single-dose primary container, impermeable to microorganisms, in which the sterile product is dosed.

Preferably, the composition of the invention is in the form of eye drops, more preferably in the form of an aqueous solution or a gel. Another aspect of the invention relates to the composition comprising an extract of Perilla for use in the treatment of diseases and/or disorders in the ophthalmic field.

Three types of formulation are preferred. A first type of composition of the invention [indicated hereinafter as Fl], which is represented by a solution with low viscosity (approximately 5 mPa*s - 15 mPa*s [Rheomat viscometer mod. L9 - 22°C]), is in turn subdivided into two formulation variants. The actions performed in the eye by the first formulation variant [indicated hereinafter as Fla] are; antioxidant, refreshing, diluent. In particular, the diluent action, which is performed by way of the dilution and subsequent removal from the ocular surface of the excess liquid by blinking, enables the dilution and removal of allergens, dust and mucoid thickening agents from the ocular surface, thus being useful for the prevention and treatment of disorders caused by such factors and for the treatment and/or prevention of allergic rhinoconjunctivitis. The actions performed in the eye by the second formulation variant [indicated hereinafter as Fib] are: antioxidant, refreshing, diluent and hydrating. In particular, the hydrating action is attributed to the presence of a percentage of hyaluronic acid that is at least twice as much as that of the first variant.

A second type of composition of the invention [indicated hereinafter as F2] is represented by a solution with medium viscosity, approximately 20 mPa^«s - 100 mPa*s [Rheomat viscometer mod. L9 - 22°C]. The actions performed in the eye are: antioxidant, hydrating, lenitive and wetting and are useful in particular for the attenuation of symptoms of dry eye due to unfavorable environmental conditions, of a moderate dry eye pathological state, of the prolonged use of contact lenses. A third type of composition of the invention [indicated hereinafter as F3] is represented by a gel with medium to high viscosity, approximately 600 mPa-s - 800 mPa*s [Rheomat viscometer mod. L9 - 22°C]. The actions performed in the eye are: antioxidant, lubricant, lenitive and supplementing of the lipidic component of the lacrimal film and they are useful in particular for the treatment of pathological dry eye.

In another aspect, the present invention relates to a single-use primary container, i.e. a phial made of plastic material that contains the formulations with extract of Perilla that are the subject matter of the present invention.

The stability characteristics of the components of the special composition of the invention that contains Perilla, together with the adoption of the single-use primary container made of plastic, and with the use of a particular production process that involves - among the various steps - partitioning under aseptic conditions, make it possible to eliminate the need for adding preservatives to the base formula.

In detail, the single-use primary container made of plastic is produced under controlled contamination conditions and subsequently, as a second step, is made sterile, usually by irradiation (gamma ray or beta ray sterilization) or alternatively with ethylene oxide (EO).

The composition according to the invention is formulated with a preparation process with controlled bacterial load that includes the steps of sampling and dispensing and mixing of the components; the subsequent partitioning step occurs under aseptic conditions. The composition that contains Perilla is sterilized by way of a filtration process (0.22 μπι); alternatively - preferably for the compositions with medium to high viscosity (600 mPa-s - 800 mPa-s) such as the gel - the production process involves both the steps of preparation and partitioning occurring under aseptic conditions; this is due to the impossibility of sterilizing the viscous composition by filtration.

The possibility of obtaining the base formula that contains Perilla without the presence of preservatives represents an advantage from several viewpoints, for example:

^■ it reduces the risks of adverse effects for the user, such as for example the ocular irritation caused by the use of the preservative itself. For example benzalkonium chloride, which is one of the preservatives most commonly used in the formulation of eyedrops, has been shown to have toxic effects in the laboratory, in experimental and clinical studies. A quaternary ammonium salt, this compound is capable of causing instability of the lacrimal film, loss of caliciform cells, conjunctival squamous metaplasia, apoptosis, deterioration of the corneal epithelium barrier and damage to the deeper ocular tissues (Reference: Prog Retin Eye Res, 2010 - PRESERVATIVES IN EYEDROPS: THE GOOD, THE BAD AND THE UGLY);

^■ it extends the range of possible user types: formulations containing Perilla without preservatives can also be indicated for contact lens wearers; in fact the preservatives present in conventional formulations on sale usually tend to accumulate on contact lenses with the consequent risk of induction of toxic reactions such as in the case of chlorhexidine (a cationic substance), for which several studies have confirmed the tendency of the eye to develop an allergy when placed in contact over long periods with chlorhexidine, which tends to bond easily to the lipid/protein deposits present on soft contact lenses (Reference: GUF [Guida all'Uso dei Farmaci - translated title: Guide to Use of Pharmaceuticals] - from the Italian- language website www.guidausofarmaci.it, in the "oculistica" [ophthalmology] clinical section);

^■ it makes it possible to use almost entirely products of natural origin thus avoiding any modification of the characteristics of the lacrimal film since the final formulation is highly biocompatible and free from the effects associated with the use of substances such as benzalkonium chloride (a cationic quaternary ammonium salt) which is the preservative most commonly used in eyedrops, and which, as previously noted, has shown toxic effects in the laboratory, in experimental and clinical studies. A quaternary ammonium salt, this compound is capable of causing instability of the lacrimal film, loss of caliciform cells, conjunctival squamous metaplasia, apoptosis, deterioration of the corneal epithelium barrier and damage to the deeper ocular tissues (Reference: Prog Retin Eye Res, 2010 - PRESERVATIVES IN EYEDROPS: THE GOOD, THE BAD AND THE UGLY);

• it eliminates the risk of negative interactions between different types of preservatives contained in formulations of ophthalmic products, a risk that is potentially high in users affected by chronic diseases that imply the prolonged use over time of products having different compositions: in particular attention is drawn to the case of patients affected by glaucoma, for which the currently preferred treatment involves the use of a product that contains prostaglandins and benzalkonium chloride as a preservative. However, such medicine can cause dryness of the eyes, and so patients usually use in addition, and for extended periods, dictated by the chronic nature of the disease, an eyedrop solution with lubricant action, usually with hyaluronic acid because of its known lubricant action. In such cases adverse reactions can be observed as a result of the precipitation of the hyaluronic acid owing to its interaction with the benzalkonium chloride (Acta Ophthalmol, 2008 - DETRIMENTAL EFFECT OF PRESERVATIVES IN EYEDROPS: IMPLICATIONS FOR THE TREATMENT OF GLAUCOMA);

^■ the risk of possible allergic reactions which can be seen in patients following the use of some ophthalmic preservatives such as Thimerosal (a mercurial compound) is obviated: in fact, many patients can exhibit hypersensitivity to Thimerosal due to the facility of coming into contact with this preservative which is very widespread being also used in fields other than ophthalmology (Reference: Contact Dermatitis, 1988 - THIMEROSAL: A HIDDEN ALLERGEN IN OPHTHALMOLOGY).

The preservative in fact is a chemical component, within the formulations commonly on sale, the purpose of which, generally, is solely to keep the proliferation of bacteria under control and, differently from other excipients, it does not contribute to increasing either the effectiveness or the tolerability of the substances contained in the formulation and, on the contrary, it has the disadvantage of being capable of provoking adverse effects in the user.

In the following examples some practical embodiments of the invention are presented, without limiting the scope thereof.

Example 1 : Formula Fla non-viscous

Components and specifications: Figure 1

%

No. COMPONENTS

W/W

1 WATER FOR INJECTABLE PREPARATIONS 98.550

Perilla DRY HYDROALCOHOLIC EXTRACT 2.5% 0.100

2

polyphenol titer

3 HYALURONIC ACID SODIUM SALT (1.5-1.7 MDA) 0.100

4 SODIUM CHLORIDE 0.480

5 Sodium dihydrogen phosphate monohydrate 0.154

6 Disodium hydrogen phosphate anhydrous 0.616

SPECIFICATIONS

appearance clear solution, from colorless to slightly yellow, with no particles in suspension

the solution ranges from odorless to slightly odorous, with a odor pleasant odor

PH 7.3 (acceptance range: 7.0 - 7.4)

osmolality 300 mOsm/kg (acceptance range: 290 - 320 mOsm/kg)

Viscosity 7 mPa-s (acceptance range: 5 mPa-s - 9 mPa-s) [measured with Rheomat viscometer mod. L9 - at a temperature of 22°C, Rl rotor, speed 8 rpm] Example 2: Formula Fib non- viscous

Example 3 : Formula F2 having medium viscosity

%

No. COMPONENTS

W/W

1 WATER FOR INJECTABLE PREPARATIONS 97.930

Perilla DRY HYDROALCOHOLIC EXTRACT 2.5% 0.100

2

polyphenol titer 3 HYALURONIC ACID SODIUM SALT (1.5-1.7 MDA) 0.250

4 VEGETABLE GLYCERIN 0.200

5 HYDROXYPROPYLMETHYLCELLULOSE 0.300

6 SODIUM CHLORIDE 0.300

7 Sodium dihydrogen phosphate monohydrate 0.350

8 Disodium hydrogen phosphate anhydrous 0.570

SPECIFICATIONS

appearance Solution of slightly gel-like consistency, clear, from colorless to slightly yellow, with no particles in suspension odor the solution ranges from odorless to slightly odorous, with a pleasant odor

PH 6.8 (acceptance range: 6.5 - 7.0)

osmolality 290 mOsm/kg (acceptance range: 270 - 300 mOsm/kg)

Viscosity 25 mPa-s (acceptance range: 20 mPa-s - 100 mPa-s)

[measured with Rheomat viscometer mod. L9 - at a temperature of 22°C, Rl rotor, speed 7 rpra]

Example 4: Gel formula F3 having medium-to-high viscosity

Components and specifications: Figure 4

The F3 formulation was studied in terms of the quality and quantity of the excipients so as to obtain a formulation that is relatively liquid under non-physiological conditions, i.e. at the pH and temperature of formulation (respectively 4.5 and ambient temperature), but which in a physiological environment, i.e. when applied on the ocular surface, undergoes a phase modification thus forming a gel that is more viscous than the initial formulation, making it possible to extend the period of time the formulation remains on the ocular surface. More precisely, Carbopol 980 has been used, which is a polyacrylic acid polymer that undergoes a transition from the liquid state to a gel when the formulation that contains it comes into contact with aqueous solutions that are capable of increasing its pH above its pK of approximately 5.5. This effect can also be obtained by inserting a combination of Carbopol and other viscosifiers, such as for example hydroxypropyl methyl cellulose (HPMC), in the formulation (Reference: The Pharmaceutical Society of Japan, 2007 - PREPARATION AND EVALUATION OF A CARBOPOL®/HPMC-BASED IN SITU GELLING OPHTHALMIC SYSTEM FOR PUERARIN and Lubrizol TDS-730 VISCOSITY OF CARBOPOL® POLYMERS IN AQUEOUS SYSTEMS). The Carbopol 980 NF gel moreover exhibits a non-Newtonian behavior, substantially pseudo-plastic (specifically Ellis plastic, reference: Lubrizol PHARMACEUTICAL BULLETIN 7 FLOW AND SUSPENSION PROPERTIES). The administration of ophthalmic preparations should interfere as little as possible with the pseudo-plastic characteristics of the precorneal film. Considering that the ocular share rate is very high (range: from 0.03 s-1 in the inter-blinking period to 4250-28, 500 s-1 during blinking), it is preferable to use viscoelastic formulations, such as the formulations with Carbopol, which are characterized by a viscosity that is high in conditions of low shear rate and low in conditions of high shear rate (Reference: Pak. J. Pharm. Ski., 2009 SUSTAINED OPHTHALMIC DELIVERY OF OFLOXACIN FROM AN ION-ACTIVATED IN SITU GELLING SYSTEM). Finally, Carbopol is a substance with mucoadhesive properties (Reference: The Pharmaceutical Society of Japan, 2007 - PREPARATION AND EVALUATION OF A CARBOPOL®/HPMC- BASED IN SITU GELLING OPHTHALMIC SYSTEM FOR PUERARIN

and Lubrizol PHARMACEUTICAL BULLETIN 23 BIOADHESION) because of its chemical nature and the high molecular weight of the polymer which rapidly swells in water, thus exposing an ample surface for contact with the ocular mucous membrane. In particular, Carbopol adheres to the mucin (glycoprotein) present on the mucous membrane of the ocular surface, although the precise mechanism whereby this occurs is not yet completely clear.

Based on the foregoing, in-vitro tests of the F3 composition have been conducted to verify and quantify the sol/gel change of state under physiological conditions, i.e. after instillation of the formulation in the eye, i.e. pH 7.4 and a temperature of 37°C.

Specifically, an aliquot of the formulation F3 (described in Figure 4) was brought to pH 7.4 with NaOH 1 M. Subsequently the sample was thermostatically heated to 37°C and its viscosity was measured, which resulted 1410 mPa-s [measured with Rheomat viscometer mod. L9 - at a temperature of 37°C, R2 rotor, speed 2 rpm], thus revealing that the viscosity of the F3 formula doubles following application on the ocular surface.

The Fl .a, Fl .b, F2 and F3 formulations described in the examples given above were subjected to a preliminary chemical/physical stability study at room temperature and at 4°C. The experimental data measured confirmed the stability of the organoleptic characteristics (appearance and odor) and of the chemical-physical characteristics (pH, osmolality and viscosity) of such formulations after 5 months of storage under environmental test conditions. Mathematical extrapolation of the stability data to a longer storage period suggests that the critical parameters defined in the specifications are kept over time.

The disclosures in Italian Patent Application No. MO2010A000369 from which this application claims priority are incorporated herein by reference.

Claims

1. A composition suitable for ophthalmic administration comprising a Perilla extract.

2. The composition according to claim 1 , wherein the extract is produced starting from leaves and seeds of at least one plant of the Perilla genus.

3. The composition according to one of the preceding claims, wherein the Perilla extract is in the form of a dry hydroalcoholic extract comprising 2.5% by weight of the total weight of the extract, of polyphenols derived from Perilla and wherein the Perilla extract is present in a percentage of from 0.1% to 5% by weight of the total weight of the composition.

4. The composition according to one of the preceding claims, further comprising hyaluronic acid sodium salt.

5. The composition according to one of the preceding claims, wherein the hyaluronic acid content is at least equal to 0.1% w/w and more preferably greater than 0.2% by weight of the total weight of the composition.

6. The composition according to one of the preceding claims, without preservatives.

7. The composition according to one of the preceding claims, in the form of eye drops.

8. The composition according to claim 7, in the form of a solution or gel.

9. A composition according to one of the preceding claims, for use in the treatment of diseases and/or disorders in the ophthalmic field.

10. The composition according to one of the preceding claims in the form of a solution having a viscosity comprised between 5 mPa-s and 9 mPa-s, for use in the prevention and treatment of disorders caused by the presence of dust and mucoid thickening agents on the ocular surface, for the treatment and/or prevention of allergic rhinoconjunctivitis.

1 1. The composition according to one of claims 1 to 9 in the form of a solution having a viscosity between 10 mPa-s and 15 mPa-s and comprising hyaluronic acid in a quantity greater than 0.2% by weight of the total weight of the composition, for use in the prevention and treatment of disorders caused by the presence of dust and mucoid thickening agents on the ocular surface, for the treatment and/or prevention of allergic rhinoconjunctivitis and for hydration of the ocular surface.

12. The composition according to one of claims 1 to 9 in the form of a solution having a viscosity between 20 mPa-s and 100 mPa-s for use in the attenuation of symptoms of dry eye due to unfavorable environmental conditions, of a moderate dry eye pathological state, of the prolonged use of contact lenses.

13. The composition according to one of claims 1 to 9 in the form of a gel having a viscosity between 600 mPa-s and 800 mPa-s for use in the treatment of pathological dry eye.

14. A single-use package comprising the composition according to one of claims 1 to 13.

15. A method for the production of a single-use package according to claim 14, wherein the composition has a viscosity lower than 600 mPa-s, comprising a step of formulation with a preparation process with controlled bacterial load, which includes the steps of sampling and dispensing and mixing the components, followed by a subsequent partitioning step that takes place under aseptic conditions after filtration (0.22 μιη) of the composition containing Perilla in order to make it sterile.

16. The method for the production of a single-use package according to claim 14, wherein the composition has a viscosity greater than 600 mPa-s, comprising the steps of formulation and partitioning in the primary container performed under aseptic conditions.