Quercetin-Based Compositions for the Treatment and Prevention of Eye Diseases - Patent application

Abstract

Compositions comprising a solid dispersion of quercetin are useful for treating and / or preventing eye diseases.

Description

[Technical field]

[0001] The present invention relates to oral compositions useful for the treatment and / or prevention of ocular affections. [Background technology]

[0002] Flavonoids, or bioflavonoids, are a class of dipolyphenolic compounds ubiquitous in plant species, and such compounds perform a variety of functions, including flower pigmentation, UV filters, and acting as chemical transmitters and physiological regulators. To date, about 5,000 types have been isolated and characterized, and can be classified into subsets such as anthocyanidins, chalcones, flavones, flavonols, flavanones, flavanonols, flavanols, flavandiols, isoflavones, isoflavans, isoflavandiols, coumestans, and pterocarpans.

[0003] Quercetin, a compound of formula 1 belonging to a subset of flavonols, is present, usually in glycosylated form, in various fruits and vegetables such as apples, berries, grapefruit, onions, capers, radishes, and their derivatives such as red wine and tea. [ka]

[0004] In vitro, quercetin has demonstrated anti-inflammatory, immunomodulatory, anti-allergic, antifibrotic, anticoagulant, antibacterial, antiatherogenic, antihypertensive and antiproliferative properties (Non-Patent Document 1).

[0005] Quercetin has low bioavailability due to its water insolubility, and its applications in the fields of dietary supplements and medicines do not reflect the potential shown in in vitro studies.

[0006] Formulation of quercetin as a solid dispersion comprising quercetin, phospholipids and a water-soluble carrier increases the solubility of quercetin, thereby widening the range of possible applications (Patent Document 1).

[0007] For the treatment and / or prevention of ocular diseases, especially those involving the ocular epithelium, topical application of medicinal agents is usually provided. Such a route of administration, even if it is the selected mode of administration, has several drawbacks. The therapeutic effect strictly depends on the ability of the drug to penetrate the ocular epithelium, and therefore is not applicable to water-insoluble drugs. Furthermore, due to the anatomical and physiological characteristics of the eye, only about 1% of the applied dose is effectively absorbed, and the remaining part is discarded by drainage and blinking, tear turnover, tear dilution, tear evaporation, induced lacrimation, enzymatic degradation or binding to tear proteins, etc. (Non-Patent Document 2). These drawbacks can lead to the need to repeat the application of the medication multiple times throughout the day, making it difficult for patients to comply with the treatment regimen. Furthermore, continuous manipulation of the eye can lead to the development of bacterial infections, for example caused by applying the medication without washing the hands beforehand, or to traumatic injuries, such as abrasion by fingernails or the tip of the medication applicator.

[0008] Patent Document 2 reports the in vitro anti-inflammatory and antioxidant activities of polyphenolic compounds such as quercetin and resveratrol, either alone or in mixtures, on human corneal epithelial cultures, and in vivo anti-inflammatory and antioxidant activities of a topical formulation in a rat animal model of the condition known as dry eye.

[0009] US Patent No. 5,399,633 discloses the preparation of an ointment for the treatment of chronic catarrhal conjunctivitis, comprising plant extracts, in particular quercetin.

[0010] US Patent No. 5,933,636 discloses a composition comprising at least a sustained release component comprising quercetin and at least an immediate release component comprising an extract of Perilla frutescens or a component contained therein.

[0011] Given the diverse biological properties exhibited by quercetin, there remains a need to identify new potential pharmaceutical and nutraceutical applications for its formulation as a solid dispersion. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2019 / 016146 [Patent Document 2] International Publication No. 2013 / 164512 [Patent Document 3] China Patent Publication No. 1110141599 [Patent Document 4] US Patent Publication No. 2017 / 258864 [Non-patent literature]

[0013] [Non-Patent Document 1] “Health effects of quercetin:from mechanism to nutraceutical,”Agnes W.Boots,2006 [Non-Patent Document 2] “Sviluppo di inserti oftalmici liofilizzati per la somministrazione di antimicrobici peptidici” [Development of lyophilized ophthalmic inserts for the administration of peptide antimicrobials],Serena Tivegna,2015 Summary of the Invention

[0014] Description of the invention: The applicant has surprisingly discovered a new use for compositions comprising quercetin, which allows the use of quercetin in the treatment and / or prevention of eye diseases.

[0015] The present invention therefore relates to the use of a composition comprising quercetin for the treatment and / or prevention of ocular diseases, in particular of the ocular epithelium, more particularly to the use of a composition comprising quercetin in the form of a solid dispersion, and even more particularly to the use of a composition comprising quercetin in the form of a solid dispersion by the oral route, for the treatment and / or prevention of diseases of the ocular epithelium.

[0016] Typically, the eye disease involves the iris, cornea, pupil, anterior chamber, lens, conjunctiva, sclera, preferably the cornea and conjunctiva.

[0017] Typically, eye disorders include conjunctivitis, allergic conjunctivitis, corneal lacerations with or without edema due to trauma or the like, superficial punctate and linear keratitis, dry eye, and other disorders such as blurred vision and eye strain associated with prolonged exposure to sources of high blue light such as computer screens and mobile phones, tablets, etc.

[0018] For the sake of clarity, in the present invention the term "ocular epithelium" refers to an ocular structure consisting of epithelial tissue such as the conjunctival or corneal epithelium, the term "affections" refers to abnormal conditions of the epithelium resulting from trauma, the intervention of a pathogen or an overreaction of the immune system, and the term "solid dispersion" refers to a system of at least two components, where at least a first component is dispersed in at least a second component, and the resulting system is physically homogeneous.

[0019] In a first aspect, the present invention relates to a composition comprising a quercetin solid dispersion for the treatment and / or prevention of ocular diseases. Such a solid dispersion comprises quercetin, a phospholipid and, optionally, a water very soluble to freely soluble carrier.

[0020] In the present invention, the terms "very soluble" and "freely soluble" have the meanings according to the European Pharmacopoeia 5.0 definitions given in Table 1 below. [Table 1]

[0021] For clarity, "very soluble" carrier means that 1 g of said carrier dissolves completely in less than 1 mL of solvent (water) at a temperature comprised between 15 and 25° C., and "freely soluble" means that 1 g of carrier dissolves completely in an amount of solvent (water) comprised between 1 and 10 mL at a temperature comprised between 15 and 25° C.

[0022] The phospholipids can be selected from soybean, sunflower or egg lecithin, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, or mixtures thereof, in which the acyl groups, which are identical or different from one another, are derived, for example, from palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid.

[0023] The weight ratio of quercetin to phospholipids may range from 5:1 to 1:1, preferably from 2:1 to 1:1.

[0024] Water very soluble to freely soluble carriers can be selected from the group consisting of mono- and disaccharides (sucrose, fructose, maltodextrin, etc.); polyhydric alcohols (mannitol, sorbitol, xylitol, etc.); oligo- and polysaccharides (dextran, pullulan, etc.).

[0025] The weight ratio of quercetin to carrier may range from 1:5 to 5:1, preferably from 1:2 to 3:1.

[0026] Typically, the composition may further comprise one or more excipients of food or pharmaceutical grade such as disintegrants, lubricants, binders, coating agents, colorants, adsorption enhancers, solubilizers, stabilizers, flavors, sweeteners, preservatives, preservatives, antioxidants, and the like.

[0027] An example of a preferred solid dispersion consists of quercetin, sunflower lecithin and maltodextrin, where the weight ratio of quercetin to sunflower lecithin is equal to 1:1 and the weight ratio of quercetin to maltodextrin is 2.2:1.

[0028] Typically, compositions containing quercetin solid dispersions are administered orally in the form of chewable tablets, capsules, soft gelatin capsules, hard gelatin capsules, lozenges, chewable lozenges, pills, tablets, orodispersible tablets, granules for oral solutions, syrups, gels, pads, drops, drinks; preferably, tablets.

[0029] With particular reference to the first preferred embodiment, the present invention relates to the use of an oral composition comprising a quercetin solid dispersion for the treatment and / or prevention of ocular diseases involving the iris, cornea, pupil, anterior chamber, lens, conjunctiva, sclera, such as conjunctivitis, allergic conjunctivitis, corneal lacerations with or without edema caused by, e.g., trauma, superficial punctate and linear keratitis, dry eye, etc.

[0030] A second preferred embodiment is represented by a combined preparation of a composition comprising a solid dispersion of quercetin and a further drug for simultaneous, separate or sequential use in the treatment and / or prevention of eye diseases; typically such drugs are selected from antiallergic agents, antibiotics, anti-inflammatory agents, analgesics, antihistamines or antivirals.

[0031] For clarity, the phrase "concurrent, separate, or sequential use in the treatment and / or prevention of ocular affections" means that a treatment and / or prevention regimen for ocular affections provides for the intake of both an oral composition comprising a quercetin solid dispersion and an additional agent, regardless of the method of administration of each.

[0032] A preferred embodiment is represented by the combined preparation of an oral composition comprising a quercetin solid dispersion and a topical antibiotic for the treatment of ocular diseases resulting from trauma.

[0033] In a study conducted by the applicant, seven subjects suffering from inflammation such as mild or severe lacerations or keratitis caused by trauma of a mechanical, thermal and chemical nature and detailed in Table 2 were treated with a broad spectrum topical antibiotic and an oral quercetin solid dispersion. In these subjects, after a period of 3-7 days, reduction in pain and scarring of the damaged tissue was observed, regardless of the type of offender. Without being bound by theory, the reduction in pain and the accelerated scarring are surprising effects that can be attributed to the administration of quercetin.

[0034] Quercetin is known to have anti-inflammatory properties due to its ability to inhibit cyclooxygenases (COXs) and lipoxygenases (LOXs) (Li Y.et al., Nutrients, 2016, 8, 167), but its effect on reducing inflammation at the ocular level is surprising. In fact, the presence of a complex system of blood-ocular barriers prevents orally administered drugs from reaching the eye in concentrations that would allow them to achieve a therapeutic effect. By formulating quercetin as a solid dispersion, not only can the bioavailability of quercetin be increased, but it can also cross the blood-ocular barrier. Usually, topical preparations containing anti-inflammatory drugs such as corticosteroids and nonsteroidal anti-inflammatory drugs are used to treat eye diseases involving inflammatory processes. In any case, such treatments can slow the scarring process of tissues and prolong healing times. The use of quercetin as an anti-inflammatory agent affects the scarring time and accelerates scarring of epithelial tissues.

[0035] A further embodiment is represented by a combination formulation of a quercetin solid dispersion with a topical antihistamine for the treatment and / or prevention of allergic conjunctivitis.

[0036] In a study conducted by the applicant, 15 subjects were treated with 2 tablets of quercetin solid dispersion and 1 drop of antibiotics in each eye twice daily for 15 days. The efficacy of the treatment was verified by measuring the TOSS questionnaire and tear film breakup time before and after the start of treatment. The TOSS ("Total Ocular Symptom Score") questionnaire is commonly used by allergists to evaluate the ocular symptoms (itchy eyes, lacrimation, conjunctival congestion, ocular congestion and photophobia) of patients with allergic conjunctivitis, assigning each symptom a value ranging from 0 to 3 depending on the severity of the symptom. As can be seen from the questionnaire results in Table 3, at the end of the study, regardless of the severity of the symptoms before treatment, in almost all cases the subjects reported disappearance of the symptoms or indicated that the symptoms were mild.

[0037] The tear break-up time was measured by the NIF-BUT test ("Non Invasive First Breakup Time") and the NIVag-BUT test ("Non Invasive Average Breakup Time"). The NIF-BUT test indicates the time in seconds and tenths of seconds that elapses from the opening of the eyes after another blink until the moment when the first break appears in the tear film or when the eyelids blink again. The NIVag-BUT test indicates the average time of tear break-up, calculated by averaging the time when all the sectors of the disc reflected on the cornea actually break and appear distorted over time. The descriptive statistics analysis of the results obtained from the two tests reported in Tables 4 and 5 showed that the tear break-up time was significantly improved. In fact, the tear break-up time increases by at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105% and 110%. Moreover, with particular reference to the results obtained with the NIF-BUT measurement, it can be seen that the tear break-up time goes from a borderline state to a normal state.

[0038] Although quercetin is known to have anti-inflammatory and anti-allergic effects (Shaik YBet al., J Biol Regul Homeost Agents. 2006, 20(3-4): 47-52; Chirumbolo S., Inflamm. Allergy-Drug Targets 2010; 9(4): 263-85), the achievement of such therapeutic effects by oral intake of quercetin is not expected for the reasons mentioned above. Moreover, the positive effect on tears is not only advantageous for reducing the discomfort of patients suffering from allergic conjunctivitis, but also seems to be advantageous for healthy subjects. For example, healthy subjects wearing contact lenses may develop dry eyes due to external factors such as central heating, wind, sun, long-term exposure to light sources with a high proportion of blue light, as the lenses absorb moisture from the tears. Such dry eyes not only require the use of tear drops, but may also cause eye irritation and lead to inflammatory phenomena.

[0039] Further unexpected effects associated with the ingestion of quercetin in the form of the solid dispersion of the present invention are represented by the fact that not only did the condition of the treated subjects improve during the two weeks of treatment, but such positive effects persisted for the next two weeks. Further unexpected effects associated with the ingestion of quercetin in the form of the solid dispersion of the present invention are represented by the fact that not only did the condition of the treated subjects improve during the two weeks of treatment, but such positive effects persisted for the next two weeks. Unlike topically administered drugs that lose their effectiveness at the end of treatment, oral ingestion of quercetin exerts its efficacy beyond the end of treatment, preventing recurrence of the eye disease studied.

[0040] With particular reference to the second preferred embodiment, the present invention relates to the use of an oral composition comprising a quercetin solid dispersion in combination with a further agent for the treatment and / or prevention of ocular diseases relating to the iris, cornea, pupil, anterior chamber, lens, conjunctiva and sclera, such as conjunctivitis, allergic conjunctivitis, corneal lacerations with or without edema caused by, e.g., trauma, superficial punctate and linear keratitis, dry eye, etc. EXAMPLES

[0041] Materials and Methods: A commercially available quercetin-based solid composition (Quercefit®, Indena SpAItaly) was administered and formulated in the form of a tablet for oral administration. The composition contains quercetin, sunflower lecithin, maltodextrin and silica. The antibiotic olopatadine 0.1% solution - Pataday®, Alcon, USA) was administered in the form of eye drops. Tear break-up time was evaluated by the NIF-BUT and NIVag-BUT tests.

[0042] Example 1 - Verification of the effectiveness of an oral composition containing quercetin in treating corneal lesions Subjects with corneal lesions of any severity were prescribed treatment with broad-spectrum topical antibiotics for a number of days depending on the type and extent of the lesion, and one oral Quercefit® tablet (250 mg / day) for 30 days. Such treatment reduced the pain associated with the corneal lesions and promoted scarring of the corneal epithelium, ranging from 3 to 7 days. Table 2 details subjects who received monotherapy.

[0043] [Table 2]

[0044] Example 2 - Examination of the efficacy of an oral composition containing quercetin in treating allergic conjunctivitis Fifteen subjects were treated with two Quercefit® tablets (500 mg / day) and one drop of olopatadine (0.1% solution) in each eye twice daily for 15 days. Primary endpoint: Change in the mean score of the "Total Ocular Symptom Score (TOSS)" questionnaire.

[0045] [Table 3] where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms, and t0 = before treatment, t 15 = End of treatment.

[0046] Secondary Endpoints: Improved tear break-up time Tear break-up time is the time, in seconds, between blinking and the appearance of the first dry spot in the tears. In non-invasive techniques, a grid or concentric circle pattern is projected onto the cornea, and the image becomes distorted as the eye begins to dry out. Tear break-up time is usually classified as normal (TBUT>10 s), borderline (10 s>TBUT>5 s), or low (TBUT<5 s). [Table 4] [Table 5]

Claims

1. A quercetin solid dispersion, a phospholipid, and A very water soluble carrier, in which 1 g of the carrier is completely dissolved in a volume of less than 1 mL of water at a temperature comprised in the range of 15 to 25° C.; or A water-free soluble carrier, comprising a carrier in which 1 g of the carrier is completely soluble in a volume of water comprised between 1 and 10 ml at a temperature comprised between 15 and 25° C.; A composition for use in the treatment and / or prevention of eye diseases.

2. The composition for use according to claim 1 , wherein the phospholipid is selected from soybean, sunflower or egg lecithin, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, or mixtures thereof.

3. 2. The composition for use according to claim 1, wherein the water very soluble to freely soluble carrier is selected from monosaccharides, disaccharides, oligosaccharides and polysaccharides.

4. The composition for use according to the preceding claims, wherein the eye disease is conjunctivitis, allergic conjunctivitis, corneal lacerations with or without edema e.g. caused by trauma, superficial punctate and linear keratitis, dry eyes, blurred vision, eye fatigue, and functional disorders associated with prolonged exposure to light sources with a high proportion of blue light.

5. A composition for use according to claims 1 to 4, which is for oral administration.

6. 6. The composition for use according to claim 5, in the form of a chewable tablet, capsule, soft gelatin capsule, hard gelatin capsule, troche, chewable troche, pill, tablet, orally disintegrating tablet, granules for oral solution, syrup, gel, pad, drop or drink.

7. The composition for use according to claims 1 to 6, comprising a further drug for simultaneous, separate or sequential use in the treatment and / or prevention of eye diseases, said further drug being selected from an antiallergic agent, an antibiotic, an anti-inflammatory agent, an analgesic agent or an antiviral agent.

Images