EA041832B1 - OPHTHALMIC COMPOSITION CONTAINING POLYUNSATURATED FATTY ACIDS - Google Patents

Description

The present invention relates to compositions for use in ophthalmology, containing one or more polyunsaturated fatty acids (PUFAs) with a free carboxyl group (CKG) in aqueous solution with methyl-v-cyclodextrins (M-v-CD), where said PUFAs are selected from the group , including omega-3 and omega-6 polyunsaturated fatty acids, the aliphatic chain of which contains from 16 to 24 carbon atoms.

Another object of the invention is the use of said composition in ophthalmology.

Prior Art

The use of polyunsaturated fatty acids (PUFAs) in pharmaceutical compositions is significantly limited due to their poor water solubility and low chemical stability inherent in these acids.

As is known, the poor solubility of PUFAs in water is easily overcome by using heterogeneous systems such as emulsions or dispersions of oils in semi-liquid aqueous media based on hydrophilic polyacrylic polymers structured like a high molecular weight polyacrylic acid crosslinked with divinyl glycol and known under the Noveon trademark, and a vinyl polymer known under the trade name Carbopol brand.

Recently, attempts have been made to prepare ophthalmic preparations with various lipophilic active ingredients with increased ocular bioavailability, lipid emulsions, which have been used for some time for parenteral use.

Thus, EP 0391369 describes the use of lipid emulsions, in particular oil-in-water emulsions, as carriers for lipophilic active ingredients. However, as applied to PUFAs as active ingredients, this method shows unsatisfactory results, since the resulting emulsion turned out to be physically unstable due to the tendency to phase and chemical separation, while the titers of eicosapentaenoic (EPA) and γ-linolenic (GLA) acids significantly decrease after a month of storage at 25 °C (EPA 96% and GLA 95%), and after four months at 4°C the content of EPA drops to 85% and GLA to 90%, which is most likely due to oxidation.

WO 2006/007510 describes topical ophthalmic compositions containing omega-3 and omega-6 fatty acids. Omega 3 and omega 6 fatty acids have been emulsified with surfactants such as polyhexylated fatty acid esters and sorbitol esters, or polysorbates such as Tween and polyethoxylated methyl glucosides such as Glucam. However, emulsified formulations based on EPA, docosahexaenoic acid (DHA) and GLA are also physically and chemically unstable.

WO 2010/106571 discloses formulations for ophthalmic use which contain PUFAs and vitamin E in acetate form. These formulations were stable for 12 months. But after 12 months, both at 4°C and at 25°C, PUFAs begin to gradually decompose in a linear fashion.

WO 2010/162894 also discloses formulations for ophthalmic use which contain PUFAs. However, studies of long-term stability over 24 months at 25°C have revealed their rapid degradation according to a polynomial law.

WO 2014/035450 discloses topical ophthalmic preparations based on omega-3 fatty acids in the form of suspensions in aqueous gel, where the gel is a weakly cross-linked carboxyl-containing polymer with enough additives in the form of ionic salts to maintain the elasticity typical of gels, t .e. the elastic modulus (G') is greater than the viscous modulus (G'') (namely, G' >5 G''). Such an ophthalmic preparation, mixed in a ratio of 2:1 to 5:1 with saline lacrimal fluid, will form a mixture with a modulus G''>G', thereby transforming from an elastic gel into a liquid of exactly the viscosity that is best suited for eyes. However, this solution is not applicable in pathological conditions that lead to disruption of the functions of the lacrimal glands, such as dry keratoconjunctivitis or dry keratitis, as well as in inflammatory conditions of the ocular surface, when the volume of the lacrimal fluid becomes much less than 6 μl (Scherz W. et al ., Tear Volume in Normal Eyes and Sicca Keratoconjunctivitis, Arbrecht v. Graefes Arch. Klin. Exp. Ophthal. 192, 141-150, 1974). Eye drops are almost always administered in volumes greater than 30 μl, and therefore the amount indicated for the diseased eye will never give a ratio of the volume of tear fluid and the volume of eye drops sufficient for the gel-sol transition. If the transition from an elastic gel to a viscous liquid does not occur, then the patient's eyelids stick together and vision is distorted. The drug is reported to be physically stable for several weeks; data on the chemical stability of the omega-3 acids contained in it are not given.

Thus, there is a strong need for PUFA-based compositions that have physical and chemical stability and at the same time good eye tolerance.

Detailed description of the invention

The object of the present invention is an aqueous solution which contains PUFAs and methyl-v-cyclodextrins as solubilizing agents. Such a composition is chemically and physically stable without the need to resort to the use of heterogeneous emulsions or suspensions in hydrogels. This composition shows a particularly great advantage in the case of non-esterified PUFAs with a free carboxyl group (PUFAs with SKG).

Preferably, such PUFAs may be omega-3 and omega-6 acids, the aliphatic chain of which contains from 16 to 24 carbon atoms. But PUFAs whose aliphatic chain contains from 18 to 24 carbon atoms can also be used.

Said composition is an aqueous solution that includes PUFA at a concentration of 0.01 to 0.10% by weight and methyl-β-cyclodextrin at a concentration of 1.0 to 10% by weight. The preferred concentration range for PUFA is from 0.02 to 0.07 wt.%, more preferably from 0.03 to 0.06 wt.%, and methyl-β-cyclodextrin from 2.0 to 8.0 wt.%.

In a preferred embodiment of the invention, said PUFAs are PUFAs with SKG. Even more preferably, said PUFAs are selected from the group consisting of EPA, DHA and GLA.

The pH value of these solutions is close to physiological and stabilized in these compositions with a buffer solution, such as phosphate, borate or citrate.

Said compositions are particularly physically and chemically stable over time.

In some embodiments, one aspect of the present invention may be implemented as a formulation comprising, in addition to PUFA and M-v-CD, viscous polymers such as Carbopol, sodium hyaluronate, hydroxypropyl methylcellulose (HPMC) or hydroxypropyl guar (HPG).

In another embodiment, said composition may also include an osmotically active additive such as mannitol, glycerin and/or trehalose.

Alternatively, said composition may include complexing compounds of the EDTA type.

In yet another embodiment, said composition comprises emollients having anti-inflammatory activity on the surface of the eye, such as, for example, adelimidrol.

In another embodiment, the specified composition may include preservatives such as ascorbyl glycoside or antimicrobial agents.

In alternative embodiments of the present invention, other active ingredients known to those skilled in the art may be included in the composition.

Compositions prepared in accordance with the present invention are intended for use primarily in eye drops and ophthalmic ointments.

Another aspect of the present invention is the use of said composition as an agent for the treatment of eye diseases, especially inflammatory diseases affecting the surface of the eye, such as, for example, blepharitis, conjunctivitis, keratoconjunctivitis, anterior uveitis.

The present invention is illustrated by the following examples, which in no way limit its essence.

Examples 1-5: compositions containing fatty acids with a free carboxyl group EPA SKG and DHA SKG and methyl-v-cyclodextrin (M-v-CD).

Examples of compositions prepared according to the present invention are presented in table. 1.

Table 1

Composition Example 1 wt.% Example 2 wt.% Example 3 wt.% Example 4 wt.% Example 5 wt.% DGK SKG 0.03 0.04 0.03 EPKSCG 0.05 0.03 0.03 Μ-β-CD 3.0 3.0 5.0 3.0 6.0 _{Na2HPO4 _} 0.1 0.1 0.1 0.1 0.1 NaH ₂ PO ₄ *2H ₂ O 0.06 0.06 0.06 0.06 0.06 Glycerol 0.9 0.9 0.9 0.9 0.9 Mannitol 1.0 1.0 1.0 1.0 1, oh EDTA-Ya ₂ *2H ₂ O 0.02 0.02 0.02 0.02 0.02 NaCl 0.2 0.2 0.2 0.2 0.2 Purified water Up to 100 Up to 100 Up to 100 Up to 100 Up to 100

The present compositions are particularly stable over time. In table. 2 and 3, for example, data on the stability of DHA SKG according to example 1 and EPA SKG according to example 3 at 25 and 40°C. The titers of these PUFAs with SCG do not fall below 95% after 24 months of storage at room temperature. Approximately the same data were obtained for the compositions presented in examples 2, 4 and 5.

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table 2

Composition Example 1 wt.% Stability 0 month in 3 months 6 months 12 months 24 months old DGK SKG 0.03 25°C % DHA SCG 100 100 99 98 95 EPC SKG - Μ-β-CD 3.0 _{Na2HPO4 _} 0.1 pH 6.8 6.8 6.8 6.8 6.7 NaH ₂ PO ₄ *2H ₂ O 0.06 Glycerol 0.9 40°C % DHA SCG 100 98 95 -- -- Mannitol 1.0 EDTA-No. ₂ *2H ₂ O 0.02 NaCI 0.2 pH 6.8 6.8 6.7 -- -- Purified water Up to 100

Table 3

Composition Example 3 wt.% Stable 0 month ev 3 months 6 months 12 months 24 months DGK SKG - 25°C % EPA SKG 100 99 99 98 96 EPC SKG 0.05 Μ-β-CD 5.0 _{Na2HPO4 _} 0.1 pH 6.9 6.9 6.8 6.8 6.8 NaH ₂ PO ₄ *2H ₂ O 0.06 Glycerol 0.9 40°C % EPA SKG 100 97 95 -- -- Mannitol 1.0 EDTA-No. ₂ *2H ₂ O 0.02 NaCI 0.2 pH 6.9 6.8 6.7 - -- Purified water Up to 100

Examples 6-10 (for comparison): esterified (ethyl esters) fatty acids EPA EE and DHA EE EE with methyl-v-cyclodextrin (M-v-CD).

Control examples of compositions for the purpose of comparison are given in table. 4.

_____________________________________________________________________Table 4

Composition Example 6 wt.% Example 7 wt.% Example 8 wt.% Example 9 wt.% Example 10 wt.% DHA EE 0.03 0.04 - - 0.03 EPEE - - 0.05 0.03 0.03 Μ-β-CD 3.0 5.0 6.0 4.0 6.0 _{Na2HPO4 _} 0.1 oh 1 oh 1 0.1 0.1 NaH ₂ PO ₄ *2H ₂ O 0.06 0.06 0.06 0.06 0.06 Glycerol 0.9 0.9 0.9 0.9 0.9 Mannitol 1.0 1, oh 1, oh 1.0 1, oh EDTA-Ya ₂ *2H ₂ O 0.02 0.02 0.02 0.02 0.02 NaCI 0.2 0.2 0.2 0.2 0.2 Purified water Up to 100 Up to 100 Up to 100 Up to 100 Up to 100

In table. 5 shows the stability data of the composition according to the control example 6. DHA EE is almost completely decomposed after 3 months.

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Table 5

Composition Example 6 wt.% Stability 0 month in 3 months DHA EE 0.03 25°C % DHA EE 100 8 EPEE - Μ-β-CD 3.0 _{Na2HPO4 _} 0.1 pH 6.8 6.7 NaH ₂ PO ₄ *2H ₂ O 0.06 Glycerol 0.9 40°C % DHA EE 100 0.5 Mannitol 1.0 EDTA-No. ₂ *2H ₂ O 0.02 NaCl 0.2 pH 6.8 6.7 Purified water Up to 100

Examples 11-15 (for comparison): EPA SKG and DHA SKG free carboxylic fatty acids with hydroxylpropyl-3-cyclodextrin (ΓΠ-β-CD), ΓΠ-γ-CD, γ-CD and sulfobutyl ether-β-cyclodextrin (SBE- β-CD).

To emphasize the unexpected benefit observed specifically in the presence of Μ-β-CD, in table. 6 shows examples of formulations with fatty acids with a free carboxyl group in the presence of hydroxypropyl-β-cyclodecrin (ΓΠ-β-CD), hydroxypropyl-y-cyclodextrin (ΓΠ-γCD), γ-cyclodextrin (γ-CD) or sulfobutyl ether β- cyclodextrin (SBE-β-CD). The indicated concentrations of β-cyclodextrins in examples 11, 14 and 15 are the minimum to solubilize the oil.

Table 6

Composition Example 11 wt.% Example 12 wt.% Example 13 wt.% Example 14 wt.% Example 15 wt.% DGK SKG 0.03 0.04 0.03 EPC SKG 0.05 0.03 0.03 ΓΠ-β-CD 5 7 GP-u-CD 5 Y-CD 5 SBE-β-CD 6 _{Na2HPO4 _} 0.1 0.1 0.1 0.1 0.1 NaH ₂ PO ₄ *2H ₂ O 0.06 0.06 0.06 0.06 0.06 Glycerol 0.9 0.9 0.9 0.3 0.9 Mannitol 1.0 1.0 1.0 1.0 1.0 3flTA-Na ₂ *2H ₂ O 0.02 0.02 0.02 0.02 0.02 NaCl 0.2 0.2 0.2 - 0.2 Purified water Up to 100 Up to 100 Up to 100 Up to 100 Up to 100

As is easy to see, formulations with cyclodextrins other than Μ-β-CD are unstable. In table. 7 shows the stability data of the composition according to example 11, the composition of which does not correspond to the present invention and is the same as the composition described in example 1, except that it contains a different cyclodextrin.

Table 7

Composition Example 11 wt.% Stable 0 month in 3 months DGK SKG 0.03 25°C % DHA SCG 100 38 EPC SKG ΓΠ-β-CD 5.0 _{Na2HPO4 _} 0.1 pH 6.8 6.8 NaH ₂ PO ₄ *2H ₂ O 0.06 Glycerol 0.9 40°C % DHA SCG 100 eleven Mannitol 1.0 EDTA-No. ₂ *2H ₂ O 0.02 NaCI 0.2 pH 6.8 6.7 Purified water Up to 100

Results similar to those obtained with ΓΠ-β-CD were obtained with sulfobutyl esters of β-cyclodextrins (not shown). In compositions with γ-cyclodextrins, instead of β-CD, insoluble aggregates were formed, which are useless in terms of obtaining homogeneous aqueous solutions of PUFAs both in the form of free acid and in the form of ethyl esters.

Examples 16-26: Compositions containing fatty acids with a free carboxyl group EPA SKG or DHA SKG and methyl-v-cyclodextrin (M-v-CD).

Stable formulations prepared in accordance with the present invention containing polyunsaturated fatty acids with a free carboxylic group and M-v-CD in the presence of viscous polymers such as carbopol, sodium hyaluronate, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl guar (HPG), as well as osmotically active additives such as mannitol, glycerin and trehalose are presented in table. 8.

Table 8

Composition Example 16 wt.% Example 17 wt.% Example 18 wt.% Example 19 wt.% Example 20 wt.% Example 21 wt.% PUFA (CKQ 0.03 0.03 0.03 0.03 0.03 0.03 Carbopol 0.2 0.2 Hyaluronate sodium 0.15 0.15 HPMC 0.5 PIP 0.5 Μ-β-CD 3.0 2.0 3.0 2.0 6.0 2 _{Na2HPO4 _} 0.1 0.1 0.1 0.1 0.1 NaH ₂ PO ₄ *2H ₂ O 0.06 0.06 0.06 0.06 0.06 Glycerol 0.9 0.5 0.9 0.9 0.9 0.7 Mannitol 1.0 1.0 1.0 1.0 Trehalose*2H ₂ O 0.5 1.0 2.0 2 EDTA- Na ₂ * 2H ₂ O 0.02 0.02 0.02 0.02 0.02 0.02 NaCI 0.2 0.2 0.2 0.2 0.2 0.1 Purified water Up to 100 Up to 100 Up to 100 Up to 100 Up to 100 Up to 100

The compositions of examples 16-21 represent another embodiment of the invention and contain additional excipients with softening effect on the surface of the eye, including adelmidrol, which also has anti-inflammatory activity and is known for its ability to control the release of mast cell mediators with anti-inflammatory effect, and preservatives, including ascorbyl glycoside used in doses from 0.005 to 0.02%. In other embodiments, these formulations also contain active ingredients with steroidal anti-inflammatory activity and non-steroidal anti-inflammatory drugs (NSAIDs),

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Claims (7)

including bromfenac, indomethacin, piroxicam, diclofenac, ketorolac, nepafenac and acetylsalicylic acid. Examples of implementation of some of these variants of the invention are presented in table. 9. Excipients tested in examples 16-26 do not impair stability PUFA, which remains comparable to that observed in PUFA-SKG compositions in the presence of Μ-β-CD. Table 9 Composition Example 22 wt.% Example 23 wt.% Example 24 wt.% Example 25 wt.% Example 26 wt.% PUFA (CKQ 0.03 0.015 0.03 0.015 0.03 Adelmidrol 0.4 0.4 0.2 0.4 0.8 sodium hyaluronate 0.15 0.15 0.15 0.1 HPMC 0.1 — 0.5 — 0.5 PIP - 0.2 - Μ-β-CD 3.0 2.0 3.0 2.0 6.0 _{Na2HPO4 0.1} 0.1 0.1 0.1 0.1 NaH ₂ PO ₄ *2H ₂ O 0.06 0.06 0.06 0.06 0.06 Glycerol 0.9 0.9 0.9 0.9 0.9 Mannitol 1.0 - -- - 1.0 Ascorbyl glucoside 0.015 0.08 0.015 - -- EDTA-No. ₂ *2H ₂ O 0.02 0.02 0.02 0.02 0.02 NaCl 0.2 0.3 0.2 0.3 0.2 Purified water Up to 100 Up to 100 Up to 100 Up to 100 Up to 100 CLAIM 1. An ophthalmic composition comprising one or more polyunsaturated fatty acids with a free carboxyl group (PUFA with CKG) selected from the group consisting of omega-3 and omega-6 polyunsaturated fatty acids, the aliphatic chain of which contains from 16 to 24 carbon atoms, in aqueous solution with methyl-β-cycle about dextrin (M-β-CD). 2. The composition according to claim 1, characterized in that the concentration of PUFA with SCG is from 0.01 to 0.10 wt.%, and the concentration of Μ-β-CD is from 1.0 to 10 wt.%. 3. The composition according to claim 1 or 2, characterized in that the concentration of PUFA with SCG is from 0.02 to 0.07 wt.% or from 0.03 to 0.06 wt.%, and the concentration of Μ-β-CD is from 2.0 to 8.0 wt.%. 4. Composition according to any one of claims 1 to 3, characterized in that said PUFAs are selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and γ-linolenic acid (GLA). 5. Composition according to any of the pi. 1-4, further comprising one or more additives selected from osmoregulators, pH regulators, preservatives, anti-inflammatory agents. 6. Composition according to any one of claims 1 to 5, comprising one or more additional active compounds. 7. Use of a composition according to any of pi. 1-6 for the treatment of eye diseases selected from the group of inflammatory diseases affecting the surface of the eye. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2