Multi-dose ophthalmic compositions

Abstract

The present invention relates to aqueous cyclodextrin compositions containing a drug / cyclodextrin complex and sorbic acid or a pharma- ceutically acceptable sorbate salt that exhibit excellent antimicrobial preservative effects at low preservative concentrations, and to aqueous ophthalmic microsuspensions containing a solid drug / cyclodextrin complex and sorbic acid or a pharma-ceutically acceptable sorbate salt that are suitable as multi-dose formulations.

Description

Detailed Description of the Invention

[0001] [Field] The present disclosure relates to aqueous cyclodextrin compositions containing a drug / cyclodextrin complex and sorbic acid or a pharma- ceutically acceptable sorbate salt that exhibit excellent antimicrobial preservative effects at low preservative concentrations, and to aqueous ophthalmic microsuspensions containing a solid drug / cyclodextrin complex and sorbic acid or a pharma- ceutically acceptable sorbate salt that are suitable as multi-dose formulations.

[0002] 〔background〕 A major obstacle in the pharmaceutical use of cyclodextrins is the inactivation of antimicrobial preservatives by complexation with cyclodextrins. This is particularly challenging for liquid aqueous-based compositions used for topical administration, for example to the skin or eye surface. Only the uncomplexed and unbound fraction of the preservative can interact with microorganisms. The fraction of the preservative complexed with cyclodextrins or solid particulates is inactive from a microbiological point of view.

[0003] In liquid pharmaceutical compositions, the concentration of preservatives should be kept relatively low, generally well below 1% (w / v). It has been shown that relatively lipophilic preservatives with a relatively high affinity for cyclodextrin are inactivated even at low cyclodextrin concentrations, while the activity of hydrophilic preservatives with a low affinity for cyclodextrin is not significantly affected (Thorsteinn Loftsson, Olof Stefansdottir, Hafrun Frioriksdottir and Orn Guomundsson, Interactions between preservatives and 2-hydroxypropyl-β-cyclodextrin, Drug Dev. Indust. Pharm. 18(13), 1477-1484, 1992).

[0004] Cyclodextrins inactivate antimicrobial preservatives by forming a preservative / cyclodextrin complex, so the concentration of the preservative needs to be increased to maintain the antimicrobial effect (Thorsteinn Loftsson, Olof Stefansdottir, Hafrun Frioriksdottir and Orn Guomundsson, Interactions between preservatives and 2-hydroxypropyl-β-cyclodextrin, Drug Dev. Indust. Pharm. 18(13), 1477-1484, 1992; Koichiro Miyajima, Masatoshi Ikuto, Masayuki Nakagaki, Interaction of short-chain alkylammonium salts with cyclodextrins in aqueous-solutions, Chemical & Pharmaceutical Bulletin, 35(1), 389-393, 1987).

[0005] The higher the affinity a given antimicrobial preservative has for cyclodextrins, the greater the preservative surplus is needed to maintain preservative effectiveness (Rene Holm, Niels Erik Olesen, Signe Dalgaard Alexandersen, Birgitte N. Dahlgaard, Peter Westh, Huiling Mu, Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations, European Journal of Pharmaceutical Sciences, 87, 22-29, 2016).

[0006] However, there are regulatory upper concentration limits for preservatives in ophthalmic drug formulations. In general, hydrophilic preservatives have a lower affinity for cyclodextrin than lipophilic preservatives. Therefore, hydrophilic preservatives are preferred in aqueous pharmaceutical formulations containing cyclodextrin as a solubilizer.

[0007] Multi-dose cyclodextrin-containing eye drops containing antimicrobial preservatives are available commercially, see Table 1.

[0008] [Table 1]

[0009] Clorocil® eye drops contain chloramphenicol (0.8% w / v) in a vehicle of boric acid, borax, benzalkonium chloride (0.01% w / v), dimethyl-β-cyclodextrin, and sodium chloride in purified water. Chloramphenicol is a broad-spectrum antibiotic that is effective in treating eye infections such as conjunctivitis and blepharitis caused by many bacteria. Thus, the preservatives used in Clorocil® consist of the active ingredient itself and benzalkonium chloride.

[0010] Voltaren® eye drops contain diclofenac sodium (0.1% w / v) in a vehicle of benzalkonium chloride (0.005% w / v), edetate disodium (0.1% w / v), 2-hydroxypropyl-γ-cyclodextrin (2% w / v), propylene glycol (2% w / v), trometamol, tyloxapol and hydrochloric acid in purified water. According to WO 1997 / 010805 A1 (Novartis AG), antimicrobial preservation of the eye drops is achieved by combining propylene glycol with benzalkonium chloride.

[0011] The compositions of these two commercially available cyclodextrin-containing eye drops demonstrate that it is possible in the art to combine two or more antimicrobial preservatives to obtain acceptable shelf life for aqueous cyclodextrin compositions. (Sodium mercurythiolate (synonym: thiomersal) is no longer permitted for use in ophthalmic products.)

[0012] There are several patent applications or patents on the inactivation of antimicrobial preservatives by cyclodextrins, either through the development of new hydrophilic preservatives or the combination of two or more preservatives to obtain acceptable effectiveness.

[0013] JP60149530A (Takeda Pharmaceutical Co., Ltd.) discloses a cyclodextrin-containing aqueous-based pharmaceutical formulation that contains a chlorhexidine derivative as an antibacterial preservative.

[0014] WO1997010805A1 (Novartis AG) discloses a preserved ophthalmic composition comprising a cyclodextrin, a quaternary ammonium salt (such as benzalkonium chloride), an alkylene glycol (such as propylene glycol) and a pharma- ceutically active compound. According to the application, the amount of cyclodextrin used may range from 0.01% (w / w) up to 20% (w / w), and the active antimicrobial preservative consists of a combination of a quaternary ammonium salt and an alkylene glycol (such as a combination of 2.0% (w / v) propylene glycol and 0.01% (w / v) benzalkonium chloride).

[0015] EP 0 877 600 B1 (Alcon Manufacturing Ltd) discloses the antimicrobial preservation of aqueous pharmaceutical compositions containing cyclodextrin. This patent describes an aqueous pharmaceutical composition containing a pharma- ceutical active compound and cyclodextrin, which is prepared by mixing boric acid and C 16It is described that the antibacterial preservative system can be used to preserve the antibacterial properties of the present invention, which includes a combination of one or more compounds selected from the group consisting of benzalkonium halide compounds, polymeric quaternary ammonium compounds, and quaternary ammonium alkylene glycol phospholipid derivatives. Thus, the combination of boric acid and one or more quaternary ammonium preservatives is used to obtain acceptable antibacterial preservation properties.

[0016] US 6 969 706 B1 (Allergan Inc.) discloses a composition comprising cyclodextrin, a guanidine-based cationic compound, and sorbic acid or sorbate. According to the claims, the concentration of sorbic acid (or sorbate) can be from 0.05% to 1% and the pH can be from 4 to 6. Efficacy tests (USP, Ph Eur-A, and Ph Eur-B Antimicrobial Preservative Efficacy Tests) showed that the combination of polyhexamethylene biguanide and sorbate was effective against the tested pathogens in all tests when the concentration of polyhexamethylene biguanide was 3 ppm or more.

[0017] US 10 463 677 B2 (Cydex Pharmaceuticals Inc.) discloses an ophthalmic composition containing latanoprost, sulfobutylether-β-cyclodextrin, and up to 0.2% (w / v) of a preservative, such as potassium sorbate or sorbic acid, parabens, or others. According to the patent, the formulation is self-preserved by the sulfobutylether-β-cyclodextrin depending on its concentration in solution, so the inclusion of a preservative in the composition is optional.

[0018] Thus, according to the prior art, more than one preservative is generally required to obtain acceptable shelf life for aqueous cyclodextrin formulations, especially for high concentrations of cyclodextrin and natural cyclodextrin.

[0019] Aqueous eye drops contained in conventional ophthalmic multi-dose containers need to be supplemented with antibacterial preservatives to prevent microbial contamination during normal storage and use, if they do not have sufficient antibacterial activity themselves, and to present a risk to patients due to infection and spoilage of the eye drops. An ideal antibacterial preservative should be compatible with the active pharmaceutical ingredient, have no pharmacological and toxicological effects, have a broad antibacterial effect, be water-soluble, do not affect the pH of the aqueous eye drop medium, be non-toxic and non-irritating, be chemically stable, withstand autoclaving, have no effect on the eye drop container, and be effective at relatively low concentrations (EM Messmer, Konservierungsmittel in der Ophthalmologie, Ophthalmologe, 109, 1064-1070, 2012). In general, ophthalmic antibacterial preservatives cannot meet all of these requirements, and most of them cause some side effects on the ocular surface. The effectiveness of antimicrobial preservatives can be reduced by the formulation and the excipients used to formulate the active ingredient in the aqueous ophthalmic vehicle. For example, in oil-in-water emulsions, lipophilic antimicrobial preservatives distribute between the oil and aqueous phases, and only the aqueous phase has any effect on the microorganisms (Alexander T. Florence and David Attwood, Physiochemical principles of pharmacy, 4 thEd., Chapter 7.3.7 Preservative availability in emulsified systems, pages 249-250, Pharmaceutical Press, London 2006). Similarly, adsorption of preservatives to the surfaces of glass and plastic containers, and to the surfaces of particles in pharmaceutical microsuspensions, reduces their effectiveness. In the development of eye drop formulations, the effectiveness of antimicrobial preservatives is tested in the final formulation and packaging and is recommended in accordance with the European Pharmacopoeia (5.1.3. Efficacy of antimicrobial preservation; European Pharmacopoeia 10.5, 2021) or USP-NF (Antimicrobial Effectiveness Testing). <51> ; United States Pharmacopeia, 2021).

[0020] There is a wide variety of antimicrobial preservatives, only a few of which are used in eye drops. In principle, preservatives can be divided into three categories: a) detergent preservatives, b) oxidizing preservatives, and c) ion-buffering preservatives (P. David Freeman and Malik Y. Kahook, Preservatives in topical ophthalmic medications: historical and clinical perspectives, Expert Rev. Ophthalmol. 4(1), 59-64, 2009).

[0021] Detergent preservatives cause bacterial cell death by disruption of the cell membrane with subsequent cell lysis. Examples of detergent preservatives include benzalkonium chloride (BAC), the most common antibacterial preservative in ophthalmic products, cetrimonium chloride, benzethonium chloride, and quaternary ammonium compounds such as chlorobutanol. Polyquaternium-1 (PolyQuad®), a quaternary ammonium compound like BAC, is also considered a detergent preservative, even though the molecule lacks hydrophobic domains. Parabens (parahydroxybenzoate esters) are also considered detergent preservatives, although their mode of action is somewhat different. Oxidizing preservatives penetrate into bacterial cells and affect cell metabolism. Examples of oxidizing preservatives include sodium perborate (GenAqua®), and stabilized oxychloro complexes (Purite®, Bio-Cide International Inc., USA). The oxychloro complexes dissociate when exposed to light to form chloride, oxygen, chlorine, chlorite, and sodium salts.

[0022] Sorbic acid is sometimes called an oxidative preservative, although its mode of action is different (Fernando Aguilar, Riccardo Crebelli, Alessandro Di Domenico, Birgit Dusemund, Maria Jose Frutos, Pierre Galtier, David Gott, Ursula Gundert-Remy, Claude Lambre, Jean-Charles Leblanc, Oliver Lindtner, Peter Moldeus, Alicja Mortensen, Pasquale Mosesso, Dominique Parent-Massin, Agneta Oskarsson, Ivan Stankovic, Ine Waalkens-Berendsen, Rudolf Antonius Woutersen, Matthew Wright and Maged Younes, Scientific opinion on the re-evaluation of sorbic acid (E 200), potassium sorbate (E 202) and calcium sorbate (E 203) as food additives, EFSA Journal, 13(6), 1-91, 2015).

[0023] The bactericidal effect of ionic buffering preservatives is also based on an oxidative mechanism. An example of an ionic buffering preservative is SofZia® (Alcon, USA), which consists of a combination of boric acid, zinc, sorbitol, and propylene glycol.

[0024] 〔overview〕 Conventional containers of multi-dose drug formulations (in other words, multi-dose compositions) are exposed to the atmosphere and its pathogens multiple times over the course of several days, and therefore it is usually necessary to include a preservative in the multi-dose composition.

[0025] The shelf life of multi-dose compositions faces challenges due to the limited number of compounds that have received regulatory approval to date, the desirability of including at least an effective concentration of preservative, and preferably including only one preservative to simplify formulation procedures and reduce or avoid incompatibilities with other excipients.

[0026] Furthermore, while developing formulations with cyclodextrin, the inventors realized that typical preservatives (such as benzalkonium chloride) are not sufficiently efficient at the recommended concentrations as preservatives for ophthalmic use, especially in multi-dose compositions.

[0027] The present disclosure provides well-preserved aqueous cyclodextrin multi-dose compositions that are advantageous in that only one antimicrobial preservative needs to be added, at concentrations that have regulatory approval and that are even in some embodiments rather low, conventional in the art and commercially available products, and in particular avoid the inclusion of other preservatives (such as benzalkonium chloride).

[0028] In one aspect, the present disclosure provides an aqueous composition comprising: a drug / cyclodextrin complex comprising a drug and α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin; and A preservative comprising or consisting essentially of sorbic acid or a pharma- ceutically acceptable sorbate salt.

[0029] In another aspect, the present disclosure provides an aqueous composition comprising: a drug / cyclodextrin complex comprising a drug and gamma-cyclodextrin; and A preservative comprising or consisting essentially of sorbic acid or a pharma- ceutically acceptable sorbate salt.

[0030] In another aspect, the present disclosure provides a method for treating a condition of the posterior and / or anterior segments of the eye in a subject in need thereof, said method comprising topically applying to the ocular surface of said subject an aqueous composition comprising a drug as an active principle according to any one of claims 1 to 23 in an amount to deliver a therapeutically effective amount of said drug to said segment or segments of the eye.

[0031] In another aspect, the present disclosure provides a method for avoiding bacterial contamination of an eye drop comprising a cyclodextrin, the method comprising adding to the eye drop a preservative-effective amount of sorbic acid or a pharma- ceutically acceptable salt thereof.

[0032] In a further aspect, the present disclosure provides a method for producing an eye drop comprising a cyclodextrin, the method comprising: (i) providing an eye drop comprising a drug / cyclodextrin complex comprising an α-cyclodextrin, a β-cyclodextrin or a γ-cyclodextrin; and (ii) adding to the eye drop an amount of sorbic acid or a pharma- ceutically acceptable salt thereof effective as a preservative.

[0033] Detailed Description Further aspects, features and advantages of the illustrative embodiments will become apparent from the following detailed description.

[0034] The patents, published applications, and scientific literature referred to in this specification establish the knowledge of those skilled in the art and are hereby incorporated by reference in their entireties to the same extent as if each was specifically and individually indicated to be incorporated by reference.

[0035] As used herein, whether as a transitional phrase or in the body of a claim, the terms "comprise(s)" and "comprising" are to be construed as having an open-ended meaning. That is, the terms are to be construed synonymously with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term "comprising" means that the composition includes at least the recited features or components, but may include additional features or components.

[0036] The terms "consists essentially of" or "consisting essentially of" have a partially closed meaning, i.e., they do not permit the inclusion of steps or features or ingredients that substantially change the essential properties of the method or composition; for example, steps or features or ingredients that significantly interfere with the desired properties of the compounds or compositions described herein; i.e., the method or composition is limited to the specified steps or materials, and those that do not substantially affect the basic and novel properties of the method or composition. The terms "consists of" and "consisting" are closed terms, permitting only the inclusion of the recited steps or features or ingredients.

[0037] As used herein, the singular forms "a," "an," and "the" specifically include the plural forms of the terms they refer to, unless the content clearly dictates otherwise.

[0038] In this specification, the term "about" is used to mean approximately, within the region, approximately, or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the stated numerical value. In general, in this specification, the term "about" or "approximately" is used to modify a numerical value above and below the stated value with a variance of 10%.

[0039] As used herein, the terms "dissolved" or "substantially dissolved" refer to the solubilization of a solid in a solution. A solid can be considered to be "dissolved" or "substantially dissolved" in a solution if the resulting solution is clear or substantially clear.

[0040] As used herein, the description of a numerical range of a variable is intended to convey that the variable can be equal to any value within that range. Thus, for a variable that is essentially discrete, the variable can be equal to any integer value in the numerical range, including the end points of the range. Similarly, for a variable that is essentially continuous, the variable can be equal to any real value in the numerical range, including the end points of the range. As an example, a variable described as having a value between 0 and 2 can be 0, 1, or 2 for an essentially discrete variable, and 0.0, 0.1, 0.01, 0.001, or any other real value for an essentially continuous variable.

[0041] In this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. As used herein, unless specifically indicated otherwise, the word "or" is used in its inclusive sense of "and / or" rather than its exclusive sense of "either / or."

[0042] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this specification pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of ordinary skill in the art. A standard reference describing the general principles of pharmacology and pharmacology is Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10 th Ed., McGraw Hill Companies Inc., New York (2001) and Remington, The Science and Practice of Pharmacy, 22 nd Ed., Philadelphia (2013).

[0043] As used herein, the term "% by weight of compound X based on the volume of the composition", also abbreviated as "% w / v", corresponds to the amount in grams of compound X that would be introduced into 100 mL of the composition.

[0044] As used herein, the term "microparticle" refers to a particle having a diameter D of 1 μm or more and about 200 μm or less. 50 The term "nanoparticle" refers to a particle having a diameter D of less than 1 μm. 50 It refers to a particle having the following structure:

[0045] As used herein, an "ocular condition" refers to a disease, illness, or other condition that affects or involves the eye, one of the parts or regions of the eye, or surrounding tissues such as the lacrimal gland. Broadly speaking, the eye includes the eyeball, the tissues and fluids that make up the eyeball, the periocular muscles (such as the scalene and rectus muscles), the portion of the optic nerve within or adjacent to the eyeball, and surrounding tissues such as the lacrimal gland and eyelids.

[0046] As used herein, an "anterior ocular condition" refers to a disease, illness, or condition that affects or involves an area or region of the anterior eye (i.e., the front of the eye), such as the periocular muscles, eyelids, lacrimal glands, or tissues or fluids of the eye that are located in front of the lens capsule or the posterior wall of the ciliary muscles. Thus, an anterior ocular condition primarily affects or involves one or more of the following: the conjunctiva, cornea, anterior chamber, iris, lens, or lens capsule, and the blood vessels and nerves that vascularize or innervate the anterior ocular area or region. Anterior ocular conditions are considered herein to extend to the lacrimal apparatus, particularly the lacrimal gland, which secretes tears, and its excretory ducts that deliver tears to the surface of the eye. Additionally, anterior ocular conditions include corneal neovascularization, including corneal neovascularization associated with corneal inflammation, including herpes simplex keratitis, herpes zoster keratitis, bacterial corneal infection, fungal corneal infection, and corneal graft rejection. Anterior ocular conditions also include iris neovascularization and neovascular glaucoma associated with retinal vein occlusion, diabetic retinopathy, other ischemic retinopathies, and carotid artery stenosis. Anterior ocular conditions also include inflammation following ocular surgery, typically following cataract surgery. More broadly, an "anterior ocular condition" is one that also affects the external ocular surface. Additionally, anterior ocular conditions affect or involve the posterior chamber, which is the narrow space between the iris and the lens.

[0047] A "posterior ocular condition" is a disease, illness, or condition that primarily affects or involves an area or region of the posterior eye, such as the retina or choroid (at a location posterior to the plane through the posterior wall of the lens capsule), vitreous body, vitreous chamber, retina, optic nerve (i.e., optic disc), and the blood vessels and nerves that vascularize or innervate the posterior ocular area or region.

[0048] Thus, posterior ocular conditions include, for example, macular degeneration (such as non-exudative age-related macular degeneration and exudative age-related macular degeneration (also known as wet age-related macular degeneration or neovascular age-related macular degeneration)); choroidal neovascularization; pachychoroidopathy; polypoidal choroidal vasculopathy; acute macular neuroretinopathy; macular edema (such as cystoid macular edema and diabetic macular edema); Behcet's disease, retinopathy, diabetic retinopathy (including proliferative diabetic retinopathy and diabetic macular edema; also including non-proliferative diabetic retinopathy); retinal artery occlusive disease; central retinal vein occlusion; branch retinal vein occlusion; sickle cell retinopathy; macular edema associated with inflammation and inflammation-related These diseases, illnesses or conditions may include such as uveal retinal disease, also known as posterior uveitis, including neovascularization associated with retinal glaucoma; sarcoidosis retinal inflammation; sarcoidosis uveitis; syphilitic uveitis; systemic lupus erythematosus-associated inflammation in the retina or retinal vessels; retinal detachment; proliferative vitreoretinopathy; ocular trauma affecting a site or location in the posterior eye; posterior ocular conditions caused or affected by ocular laser treatment; posterior ocular conditions caused or affected by photodynamic therapy; photocoagulation; radiation retinopathy; epiretinal membrane disorder; branch retinal vein occlusion; and anterior ischemic optic neuropathy.

[0049] One aspect of the present disclosure relates to ophthalmic compositions for local drug delivery to the eye and methods for the treatment of posterior ocular conditions. In a preferred embodiment, the ophthalmic compositions are for use in treating, for example, diabetic retinopathy (including background diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema); age-related macular degeneration (AMD) (including neovascular (wet / exudative) AMD, dry AMD, and geographic atrophy); pathologic choroidal neovascularization (CNV) by any mechanism (i.e., high myopia, trauma, sickle cell disease, ocular histoplasmosis, vascular muscle, traumatic choroidal rupture, optic nerve drusen, and some retinal dystrophies); pathologic choroidal neovascularization (CNV) by any mechanism (i.e., sickle cell retinopathy, retinopathy of prematurity, Ealing, and some retinal dystrophies); It is used for the treatment of pathological conditions caused by or exacerbated by ocular neovascularization and vascular leakage in: pathologic retinal neovascularization due to ocular ischemia syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic obliterative arteritis, bird's eye chorioretinopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis; uveitis; retinal vein occlusion (central or branch); ocular trauma; surgery-induced edema; surgery-induced neovascularization; cystoid macular edema; ocular ischemia; retinopathy of prematurity; Coats' disease; sickle cell retinopathy and / or neovascular glaucoma.

[0050] In another embodiment, the ophthalmic compositions may be used for the treatment of pre-ocular conditions, including inflammation following ophthalmic surgery, typically following cataract surgery.

[0051] As immediately disclosed, the aqueous composition is an ophthalmically acceptable medium. The term "ophthalmically acceptable medium" is intended to mean a medium suitable for topical ophthalmic administration of the composition, for example in the form of an aqueous ophthalmic microsuspension containing at least 60% (w / v) purified water. In a particular embodiment, the aqueous composition is an unbuffered aqueous ophthalmic vehicle. In another particular embodiment, the aqueous composition may be a true solution. In a particular preferred embodiment, the aqueous composition is a multi-dose composition.

[0052] Sorbic acid The compositions of the present disclosure include sorbic acid and its salts, such as potassium sorbate, sodium sorbate, and calcium sorbate. The chemical name of sorbic acid is (2E,4E)-hexa-2,4-dienoic acid (molecular weight: 112.12 g / mol), and synonyms include trans,trans-2,4-hexadienoic acid, 2,4-hexadienoic acid (E,E), and (E,E)-1,3-pentadiene-1-carboxylic acid. Sorbic acid is a white, free-flowing powder. Sorbic acid is somewhat lipophilic (LogP (オクタノール / 水) =1.3), slightly soluble in water and soluble in ethanol. The melting point of sorbic acid is 133 °C-135 °C, and its pKa is 4.76. Monographs for sorbic acid and potassium sorbate materials usable in pharmaceutical compositions are included in both the European Pharmacopoeia 10.7 and the United States Pharmacopoeia / National Formulary (USP43-NF38).

[0053] [ka]

[0054] Sorbate inhibits microbial growth by inducing changes in cell membrane morphology, integrity, and function, and by inhibiting transport functions and metabolic activity. Sorbate is also known to inhibit the in vitro activity of many enzymes, especially those containing sulfhydryl groups. Other mechanisms of action have also been proposed (Fernando Aguilar, Riccardo Crebelli, Alessandro Di Domenico, Birgit Dusemund, Maria Jose Frutos, Pierre Galtier, David Gott, Ursula Gundert-Remy, Claude Lambre, Jean-Charles Leblanc, Oliver Lindtner, Peter Moldeus, Alicja Mortensen, Pasquale Mosesso, Dominique Parent-Massin, Agneta Oskarsson, Ivan Stankovic, Ine Waalkens-Berendsen, Rudolf Antonius Woutersen, Matthew Wright and Maged Younes, Scientific opinion on the re-evaluation of sorbic acid (E 200), potassium sorbate (E 202) and calcium sorbate (E 203) as food additives, EFSA Journal, 13(6), 1-91, 2015).

[0055] In certain embodiments, the aqueous composition of the present disclosure contains only sorbic acid or a pharma- ceutically acceptable sorbic acid salt as an antimicrobial preservative. No additional preservatives are added. Thus, the preservative used in the aqueous composition of the present disclosure consists essentially of sorbic acid or a sorbic acid salt. In some examples, the preservative consists essentially of sorbic acid or a sorbic acid salt.

[0056] In certain embodiments, the antimicrobial preservative does not comprise a conventional topical ophthalmic antimicrobial compound selected from the group consisting of benzalkonium chloride, benzethonium chloride, butyl-para-hydroxybenzoate, chlorobutanol, methyl-para-hydroxybenzoate, polyguaternium-1, propyl-para-hydroxybenzoate, or an oxidizing antimicrobial preservative comprising perborate, zinc, or chlorite ions.

[0057] Cyclodextrin Cyclodextrins are cyclic oligosaccharides composed of (α-1,4)-linked D-glucopyranose units. The most common natural cyclodextrins, and the only natural cyclodextrins used in pharmaceutical products, are α-cyclodextrin (α-cyclodextrin), β-cyclodextrin (β-cyclodextrin), and γ-cyclodextrin (γ-cyclodextrin), which are composed of 6, 7, and 8 D-glucopyranose units. Cyclodextrins are doughnut-shaped molecules with a hydrophilic outer surface and a somewhat lipophilic central cavity.

[0058] In aqueous solution, cyclodextrins can form water-soluble inclusion complexes with lipophilic poorly soluble drugs by incorporating some of the lipophilic sites of the drug into the central cavity (P. Jansook, N. Ogawa and T. Loftsson, 2018. Cyclodextrins: structure, physicochemical properties and pharmaceutical applications. International Journal of Pharmaceutics 535, 272-284). In aqueous solution, drug / cyclodextrin complexes are in dynamic equilibrium between dissolved drug molecules and cyclodextrin molecules. The rates of formation and dissociation of drug / cyclodextrin complexes are very close to the diffusion-controlled limit, and drug / cyclodextrin complexes are constantly forming and dissociating in aqueous solutions (Marcus E. Brewster, Thorsteinn Loftsson, 2007. Cyclodextrins as pharmaceutical solubilizers, Advanced Drug Delivery Reviews, 59(7), 645-66; VJ Stella, VM Rao, EA Zannou, V. Zia, 1999. Mechanisms of drug release from cyclodextrin complexes, Advanced Drug Delivery Reviews, 36(1), 3-16).

[0059] Due to their cyclic structure and intramolecular hydrogen bond formation, the three natural cyclodextrins and their complexes are much less soluble in aqueous solutions than linear oligosaccharides of comparable molecular weight. Like starch, cyclodextrins can also be reacted with various reagents to obtain water-soluble cyclodextrin derivatives. For example, hydroxypropylated cyclodextrin derivatives such as 2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin can be obtained by treating natural cyclodextrin with propylene oxide, sulfobutylether β-cyclodextrin and sulfobutylether γ-cyclodextrin can be obtained by treating natural cyclodextrin with 4-butane sultone, and randomly methylated cyclodextrins such as randomly methylated β-cyclodextrin can be obtained by treating natural cyclodextrin with methyl iodide.

[0060] In certain embodiments, the compositions of the present disclosure include α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin consisting of 6, 7, and 8 D-glucopyranose units. In certain embodiments, the compositions preferably include γ-cyclodextrin consisting of 8 D-glucopyranose units.

[0061] The present disclosure more specifically relates to compositions comprising nanoparticles and (preferably) microparticles having native γ-cyclodextrin and consisting of a drug / γ-cyclodextrin complex (P. Saokham, T. Loftsson, γ-Cyclodextrin, International Journal of Pharmaceutics, 517, 278-292, 2017).

[0062] Typically, the amount of cyclodextrin in the aqueous composition may be from 1% to 35%, particularly 5% to 30%, and more particularly 10% to 25%, by weight of cyclodextrin based on the volume of the composition.

[0063] It has now been surprisingly discovered that aqueous cyclodextrin formulations containing relatively high concentrations of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, particularly natural γ-cyclodextrin, can be preserved without the need to include additional antimicrobial preservatives by including sorbic acid or sorbate salts at concentrations not exceeding those found in currently commercially available aqueous eye drops. The aqueous compositions of the present disclosure may include only sorbic acid or sorbate salts as preservatives. In certain embodiments, no additional antimicrobial preservatives are added. Thus, in certain embodiments, the preservatives used in the aqueous compositions consist essentially of sorbic acid or sorbate salts. In some instances, the preservatives consist of sorbic acid or sorbate salts. Sorbic acid and sorbate salts have antioxidant activity and can stabilize the pH of aqueous drug formulations, such as aqueous corticosteroid eye drop suspensions, under certain conditions. More specifically, sorbic acid and sorbate salts can stabilize the pH of aqueous eye drop suspensions that include solid complexes of dexamethasone and γ-cyclodextrin.

[0064] In certain embodiments, the composition does not comprise a conventional topical ophthalmic antimicrobial agent selected from the group consisting of benzalkonium chloride, benzethonium chloride, butyl-para-hydroxybenzoate, chlorobutanol, methyl-para-hydroxybenzoate, polyguaternium-1, propyl-para-hydroxybenzoate, or an oxidizing antimicrobial preservative including perborate, zinc, or chlorite ions.

[0065] Drugs The aqueous composition of the present disclosure comprises a drug and can be either for human or animal use. In the context of the present disclosure, the drug is preferably an ophthalmic drug, i.e., a compound that shows a therapeutic effect when administered topically to the ocular surface in sufficient amount to a patient suffering from an ocular condition. The antimicrobial preservative composition disclosed in the present invention is also suitable for any other aqueous formulation utilized for topical use, such as dermatology (for skin and nails), otolaryngology and laryngology (for ear, nose and mouth), proctology and gynecology.

[0066] Examples of ocular conditions that may be treated by the compositions and methods of the present invention include, but are not limited to, uveitis, macular edema, macular degeneration, retinal detachment, ocular tumors, fungal or viral infections, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, and vascular occlusion.

[0067] Active agents for use in the ophthalmic compositions of the present invention may be selected from the group consisting of angiotensin-converting enzyme inhibitors (ace inhibitors), kinase inhibitors, agents affecting the basement membrane, agents affecting endothelial cell proliferation, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergic agents, anti-inflammatory agents, steroids (such as steroidal anti-inflammatory agents), antihypertensive agents, sedatives, antibacterial agents, antiviral agents, antifungal agents, antiparasitic agents, antiglaucoma agents, antiinfective agents, antitumor agents, antimetabolites, and angiogenesis inhibitors. Other drugs include chloride channel activators (for dry eye disease), NLRP3 inflammasome small molecule inhibitors for the treatment of inflammatory diseases (e.g., MCC-950), echothiopate iodine (cholinesterase inhibitors for glaucoma), and atropine (for conjunctival goblet cell stimulation and mucin formation in the conjunctiva).

[0068] Steroidal anti-inflammatory agents that can be used in the ophthalmic compositions and methods of the invention include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximethasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, etiprednol, dicloacetate, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisone, zolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbonate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and any derivatives thereof having anti-inflammatory activity. Nonsteroidal anti-inflammatory agents that may be used include, but are not limited to, aspirin, bromfenac, diclofenac, flurbiprofen, ibuprofen, indomethacin, ketorolac, naproxen, nepafenac, and suprofen.

[0069] Ace inhibitors (i.e., angiotensin-converting enzyme inhibitor drugs) that may be used in the ophthalmic compositions and methods of the present invention include, but are not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril.

[0070] Kinase inhibitors (anti-VEGF) that may be used in the ophthalmic compositions and methods of the present invention include acrizanib, afatinib, alectinib, altiratinib, anlotinib, apatinib, avapritinib, axitinib, bosutinib, brivanib, cabozantinib, calabrutinib, cediranib, crizotinib, dacomitinib, dasatinib, dovitinib, entrectinib, erlotinib, foretinib, fruquintinib, golvatinib, gilteritinib, ibrutinib, imatinib, lapatinib, lenvatinib, linifanib, midostaurin, motesanib, neratinib, nilotinib, ninten ... These include, but are not limited to, danib, orantinib, pacritinib, pazopanib, pexidartinib, ponatinib, quizartinib, regorafenib, semaxatinib, sitravatinib, sorafenib, sunitinib, surufatinib, telatinib, tivozanib, tucatinib, vandetanib, vatalanib, zanubrutinib, and ziv-aflibercept, as well as 2-D08, AZD2932, BAW2881, BFH772, BMS-794833, CYC116, Ki8751, LY2874455, MGCD-265 and its analogs, OSI-930, PD173074, RAF-265, SU5402, and ZM 323881.

[0071] Vanilloid receptor (TRPV1) antagonists that may be used in the ophthalmic compositions and methods of the present invention include thiourea analogs such as PHE-377, JNJ-38893777, MR-1817, XEN-D0501, capsazepine, and the like, urea analogs (such as A-425619, GRC-6211, V116517, SB-705498, and JNJ-17203212), cinnamide analogs (such as SB-366791, ashibatrep (PAC-1 4028) and AMG-9810), quinazolinone analogs (such as AMG-517, SAF312 (libvatrep) and MK-2295), benzimidazole analogs (such as ABT-102, AMG-2674, A-784168, mavatrep (JNJ-39439335), DWP05195 and ACD440), and imidazolidine analogs (such as AZD-1386).

[0072] Angiotensin II receptor antagonists (i.e., sartans) that may be used in the ophthalmic compositions and methods of the present invention include, but are not limited to, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan.

[0073] Carbonic anhydrase inhibitors that may be used in the ophthalmic compositions and methods of the present invention include, but are not limited to, acetazolamide, brinzolamide, dorzolamide, ethoxzolamide, and methazolamide.

[0074] Anti-glaucoma and ocular hypotensive agents that may be used in the ophthalmic compositions and methods of the present invention include, but are not limited to, prostaglandin analogs (such as bimatoprost, latanoprost, travoprost, tafluprost, latanoprost-bunod, and NCX-470), beta-blockers (such as carteolol, timolol, betaxolol, and levobunolol), and carbonic anhydrase inhibitors (such as acetazolamide, metipranolol, methazolamide, dorzolamide, brinzolamide, diclophenamide, ethoxzolamide, and zonisamide), or any combination thereof.

[0075] Antibacterial agents that may be used in the ophthalmic compositions and methods of the present invention include, but are not limited to, tigecycline, ofloxacin, metronidazole, clarithromycin, clindamycin, chloramphenicol, rifampicin, azithromycin and isoniazid.

[0076] Antifungal agents that may be used in the ophthalmic compositions and methods of the present invention include, but are not limited to, isavuconazole, voriconazole, and caspofungin.

[0077] Antiviral drugs that may be used in the ophthalmic compositions and methods of the present invention include, but are not limited to, zidovudine, sorbudine, famiclovir, babaticlovir, acyclovir, ganciclovir, rimantadine, amprenavir, atazanavir, indinavir, nelfinavir, saquinavir, tipranavir, abacavir, and nevirapine.

[0078] Immunomodulatory agents such as cyclosporine, tacrolimus, everolimus, pimecrolimus, temsirolimus, and sirolimus.

[0079] In a preferred embodiment, the aqueous composition of the present disclosure, in which a drug, preferably a poorly water-soluble drug, is complexed with a cyclodextrin, may be advantageously used as a topical formulation for treating posterior ocular conditions.

[0080] In a preferred embodiment, the aqueous composition of the present disclosure comprises a steroid, preferably dexamethasone.

[0081] The amount of the active pharmaceutical ingredient in the composition may be 0.001% (w / v) to 10% (w / v), preferably 0.1% (w / v) to 5% (w / v), more preferably 0.5% (w / v) to 4% (w / v), and even more preferably 1% (w / v) to 3% (w / v) by weight of the active pharmaceutical ingredient based on the volume of the composition. In certain embodiments, the concentration of dexamethasone may be 0.001% (w / v) to 10% (w / v), preferably 0.1% (w / v) to 5% (w / v), more preferably 0.5% (w / v) to 4% (w / v), and even more preferably 1% (w / v) to 3% (w / v) by weight of the active pharmaceutical ingredient based on the volume of the composition.

[0082] Drug / Cyclodextrin Microsuspension In certain embodiments, the aqueous composition is an aqueous microsuspension comprising microparticles of a solid drug / cyclodextrin complex suspended in an aqueous medium. As used herein, the term "microparticle" refers to a microparticle having a diameter D of about 1 μm to about 200 μm. 50 The term "nanoparticle" refers to a particle having a diameter D of less than 1 μm. 50 In an exemplary embodiment, the diameter D of the microparticle 50 is 1 μm or more to about 200 μm, in particular 1 μm to about 100 μm; the nanoparticles have a D of less than about 1 μm 50 has.

[0083] In particular, the aqueous composition of the present disclosure has a diameter D of less than about 100 μm, in particular from about 1 μm to about 100 μm. 50 In one embodiment, the microsuspension comprises solid aggregates of a drug / cyclodextrin complex having a diameter D 50 may be within the range of about 1 μm to about 50 μm, particularly about 1 μm to about 30 μm, and more particularly about 1 μm to about 25 μm.

[0084] In accordance with the present disclosure, the diameter D50 is measured by laser diffraction particle size analysis. In general, there are limited techniques for measuring / assessing the diameter and / or size of cyclodextrin / drug particles or complexes. In particular, those skilled in the art know that physical properties (e.g., particle size, diameter, average diameter, average particle size, etc.) are typically evaluated / measured using such limited typical known techniques. For example, such known techniques are described in Int.J.Pharm.493(2015),86-95, the entire contents of which are incorporated herein by reference. Additionally, such limited known measurement / assessment techniques are known in the art as evidenced by other references, such as, for example, the European Pharmacopoeia (2.9.31 Particle size analysis by laser diffraction, Jan 2010), and Saurabh Bhatia, Nanoparticles types, classification, characterization, fabrication methods and drug delivery applications, Chapter 2, Natural Polymer Drug Delivery Systems, PP. 33-94, Springer, 2016, which are also incorporated herein by reference in their entireties.

[0085] A preferred method for producing a microsuspension using solid aggregates of a drug / cyclodextrin complex is described, for example, in WO2018 / 100434, the contents of which are incorporated herein in their entirety.

[0086] In particular, 60-95% by weight, more particularly 70-90% by weight, of the drug in the composition may be in the form of a solid complex of drug and cyclodextrin. More particularly, 5-40% by weight, particularly 10-30% by weight, of the drug in the composition may be in dissolved form. Dissolved forms include uncomplexed drug that is dissolved in the liquid phase, and drug-cyclodextrin complexes that are dissolved in the liquid phase, as well as water-soluble nanoparticles consisting of aggregates of drug / cyclodextrin complexes.

[0087] Preferably, 0% to 0.5% by weight of the drug in the composition may be in uncomplexed solid form. Thus, the compositions of the present disclosure may be substantially free of solid uncomplexed particles of drug.

[0088] In one embodiment, the microsuspension can contain about 70% to about 99% of the drug in microparticles and about 1% to about 30% of the drug in nanoparticles. More specifically, the microsuspension can contain about 80% to about 95% of the drug in microparticles having a diameter of about 1 μm to about 100 μm and about 20% to about 5% of the drug in nanoparticles. The microsuspension can contain about 80% of the drug in microparticles having a diameter of about 1 μm to about 100 μm and about 20% of the drug in nanoparticles.

[0089] In another embodiment, the microsuspension can contain about 40% to about 99% of the drug in microparticles and about 1% to about 60% of the drug in nanoparticles or water-soluble drug / cyclodextrin complexes. In particular, the microsuspension can contain about 80% to about 95% of the drug in microparticles having a diameter of about 1 μm to about 100 μm, and about 5% to about 20% of the drug in nanoparticles or water-soluble active pharmaceutical ingredient / cyclodextrin complexes.

[0090] According to a preferred embodiment, the aqueous composition of the present disclosure is a microsuspension comprising solid aggregates of a drug / cyclodextrin complex, preferably a corticosteroid / cyclodextrin complex, more preferably a dexamethasone / γ-cyclodextrin complex.

[0091] The aqueous composition of the present disclosure may further comprise a polymer.

[0092] In particular, the polymer may be a water-soluble polymer. Moreover, the polymer may be a surface-active polymer. The term "surface-active polymer" is intended to mean a polymer that exhibits surface-active properties that allow it to reduce the surface tension of the entire formulation. The polymer enhances the physical stability of the composition. Surface-active polymers may, for example, comprise hydrophobic chains grafted to a hydrophilic backbone polymer; hydrophilic chains grafted to a hydrophobic backbone; or alternating combinations of hydrophilic and hydrophobic segments. The first two types are called graft copolymers, and the third type is called block copolymers.

[0093] In one embodiment, the composition comprises a polymer selected from the group consisting of polyoxyethylene fatty acid esters; polyoxyethylene alkyl phenyl ethers; polyoxyethylene alkyl ethers; cellulose derivatives (such as alkyl celluloses, hydroxyalkyl celluloses, and hydroxyalkyl alkyl celluloses); carboxyvinyl polymers (such as carbomers and polycarbophils), such as Carbopol® 971, Carbopol® 974, and Noveon® AA1; polyvinyl polymers; polyvinyl alcohol; polyvinylpyrrolidone; copolymers of polyoxypropylene and polyoxyethylene; tyloxapol; and combinations thereof.

[0094] Hyaluronic acid or sodium hyaluronate (reticulated natural), chitosan, xanthan gum, gellan gum, sodium alginate, or other polymers with viscosity enhancing activity such as iota-carrageenan.

[0095] Examples of suitable polymers include polyethylene glycol monostearate, polyethylene glycol distearate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene lauryl ether, polyoxyethylene octyldodecyl ether, polyoxyethylene stearyl ether, polyoxyhydroxystearate (Kolliphor® HS15, available from BASF), polyoxyethylene myristyl ether, polyoxyethylene oleyl ether, sorbitan esters, polyoxyethylene hexadecyl ether (e.g., cetomacrogol 1000), polyoxyethylene castor oil derivatives (Kolliphor® EL or Kolliphor® RH40, available from BASF), polyoxyethylene sorbitan fatty acid esters (e.g., Tween® 20 and Tween® 80 (ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowax® 3550 and 934 (Union Pharmaceuticals, Inc.) Carbide), polyoxyethylene stearate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, cellulose, polyvinyl alcohol (PVA), poloxamers (e.g., Pluronics® F68 and FI08, which are block copolymers of ethylene oxide and propylene oxide); polyoxamines (e.g., Tetronic® 908, also known as poloxamine 908, is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ).)); Tetronic® 1508 (T-1508) (BASF Wyandotte Corporation), Tritons X-200 (Rohm and Haas), which is an alkylaryl polyether sulfonate; PEG-derivatized phospholipids, PEG-derivatized cholesterol, PEG-derivatized cholesterol derivatives, PEG-derivatized vitamin A, PEG-derivatized vitamin E, random copolymers of vinylpyrrolidone and vinyl acetate, combinations thereof, and the like.

[0096] Tyloxapol is a 4-(1,1,3,3-tetramethylbutyl)phenol polymer containing formaldehyde and oxirane.

[0097] More specifically, the copolymer of polyoxypropylene and polyoxyethylene may be a triblock copolymer having a hydrophilic block (polyoxyethylene)-hydrophobic block (polyoxypropylene)-hydrophilic block (polyoxyethylene) structure, also called a poloxamer.

[0098] In one embodiment, the composition of the present disclosure includes a polymer that is a poloxamer. The poloxamer can include any type of poloxamer known in the art. Poloxamers include poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 23 ... poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, poloxamer 407, poloxamer 105 benzoate, and poloxamer 182 benzoate.

[0099] A particularly useful polymer as a stabilizer is poloxamer, preferably poloxamer 407.

[0100] Preferred polymers are poloxamers, tyloxapols, polyalkylene glycols, hydroxyalkyl celluloses, hydroxyalkyl alkyl celluloses, polyvinyl alcohols, polyoxyethylene ethers, sodium carboxymethylcellulose, polyethylene glycols, 12-hydroxystearate, polyoxyethylene sorbitan monooleate. Particularly preferred polymers are hydroxypropyl methylcellulose (HMPC), sodium carboxymethylcellulose MW 250 kDa, and hydroxyethyl cellulose.

[0101] The amount of polymer in the composition may be from 0.1% (w / v) to 5% (w / v), particularly from 0.3% (w / v) to 3% (w / v), more particularly from 0.5% (w / v) to 2% (w / v), by weight of polymer based on the volume of the composition.

[0102] Antioxidants The aqueous composition may contain additives to prevent oxidation of the drug.

[0103] In a preferred embodiment, the additive for preventing oxidation of the drug is selected from an antioxidant, an oxygen scavenger, a chelating agent, and mixtures thereof.

[0104] Antioxidants typically include phenolic antioxidants and reducing agents. Phenolic antioxidants are sterically hindered phenols that react with free radicals to inhibit oxidation reactions. Phenolic antioxidants can include butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Reducing agents are compounds that have a lower redox potential than the drug they are intended to protect against. Reducing agents scavenge oxygen in the medium, slowing or preventing oxidation. Reducing agents can include sodium thiosulfate (STS).

[0105] Phenolic antioxidants and reducing agents added to the composition to prevent oxidation of the drug or excipients may be added at a concentration of at least 0.05% (w / v), preferably 0.05% (w / v) to 1% (w / v), more preferably 0.1% (w / v) to 0.5% (w / v), 0.1% (w / v) to 0.45% (w / v), 0.2% (w / v) to 0.4% (w / v), 0.2% (w / v) to 0.35% (w / v), or 0.2% (w / v) to 0.3% (w / v), preferably 0.3% (w / v) to 0.5% (w / v). In certain embodiments, antioxidants, such as sodium thiosulfate, may not be added to the composition.

[0106] Chelating Agents Chelating agents are compounds that chelate metal ions, such as copper and iron, that catalyze the oxidation of active pharmaceutical ingredients or excipients used to form pharmaceutical products. Chelating agents can also enhance the antioxidant activity of tocopherol or phenolic compounds, resulting in a synergistic antioxidant effect. Examples of chelating agents include divalent and polyvalent carboxylic acids and their salts. Preferred examples include ethylenediaminetetraacetic acid (EDTA), 2,2',2''-nitrilotriacetic acid (NTA), iminodisuccinic acid (IDS), polyaspartic acid, S,S-ethylenediamine-N,N'-disuccinic acid (EDDS), methylglycinediacetic acid (MGDA), L-glutamic acid N,N-diacetic acid, phosphoric acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, and citric acid, and their salts. A preferred chelating agent is EDTA. In an exemplary embodiment, the EDTA may be ethylenediaminetetraacetic acid disodium salt.

[0107] The amount of chelating agent in the composition may be 0.01% (w / v) to 5% (w / v), 0.05% (w / v) to 3% (w / v), or 0.07% (w / v) to 2.5% (w / v), 0.1% (w / v) to 2% (w / v), 0.1% (w / v) to 1% (w / v), or 0.1% (w / v) to 0.5% (w / v) by weight of the chelating agent based on the volume of the composition. In a preferred embodiment, the amount of chelating agent (e.g., EDTA) may be 0.05% (w / v) to 0.5% (w / v), preferably 0.1% (w / v) to 0.5% (w / v). In certain embodiments, EDTA may be absent.

[0108] pH of the composition The compositions typically have a pH in the range of 3.5 to 9, preferably 4.0 to 6.5, more preferably 5.0 to 6.0, which is the range in which many chemicals exhibit maximum chemical stability. For compositions containing dexamethasone, the pH is in the range of 4.0 to 6.0, preferably 4.3 to 5.7, more preferably 4.5 to 5.5.

[0109] In some embodiments, buffer salts may be included to control the pH of the aqueous composition.Such buffer salts may include, for example and without limitation, acetic acid, sodium acetate, adipic acid, ammonium chloride, benzoic acid, sodium benzoate, boric acid, sodium bicarbonate, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, tris-hydroxymethylaminomethane, sodium tartrate, sodium citrate anhydrous and dehydrate, and others known to those skilled in the art, salts of any of the above, and combinations thereof.

[0110] Tonicity agents In certain embodiments, the composition may include an isotonicity agent used to render the composition essentially isotonic. The composition typically has an osmolality of 200 to 450 milliosmoles per kilogram (mOsm / kg), more preferably 240 to 360 mOsm / kg. Examples of suitable isotonicity agents include sodium chloride, potassium chloride, mannitol, sorbitol, dextrose, glycerin, and combinations thereof. Preferably, the electrolyte is sodium chloride.

[0111] The amount of tonicity agent in the composition of the present disclosure may be 0.01% to 5% by weight of the tonicity agent based on the volume of the composition. The concentration range may depend on the type of tonicity agent. For electrolytes such as sodium chloride and potassium chloride, the concentration range may be 0.01% (w / v) to 0.9% (w / v), or 0.1% (w / v) to 0.7% (w / v), or 0.3% to 0.7%, and for non-electrolytes such as mannitol and glucose, the range may be 0.1% (w / v) to 5% (w / v).

[0112] Antibacterial Preservatives As mentioned above, the aqueous composition of the present disclosure includes sorbic acid or / and its salts, including, but not limited to, antimicrobial preservatives such as potassium sorbate, sodium sorbate, and calcium sorbate. The amount of sorbic acid or its salts in the composition may be 0.01% (w / v) to 5% (w / v), particularly 0.1% (w / v) to 2% (w / v), more particularly 0.2% (w / v) to 1% (w / v), and preferably 0.2% (w / v) to 0.8% (w / v), by weight of sorbic acid or sorbate relative to the volume of the composition.

[0113] The aqueous composition of the present disclosure contains only sorbic acid or a sorbic acid salt as a preservative. No additional antimicrobial preservative is added. Thus, the preservative used in the aqueous composition of the present disclosure essentially consists of sorbic acid or a sorbic acid salt. In some examples, the antimicrobial preservative consists of sorbic acid or a sorbic acid salt.

[0114] The antimicrobial preservative does not include a conventional topical ophthalmic antimicrobial agent selected from the group consisting of benzalkonium chloride, benzethonium chloride, butyl-para-hydroxybenzoate, chlorobutanol, methyl-para-hydroxybenzoate, polyguaternium-1, propyl-para-hydroxybenzoate, or an oxidizing antimicrobial preservative including perborate, zinc or chlorite ions.

[0115] Manufacturing method The compositions of the present disclosure can be prepared by suspending the individual components in water to form an essentially clear solution, then heating in a closed container at 121°C for about 20 minutes. The solution is then allowed to cool to ambient temperature before equilibrating at 22-23°C under constant agitation. During equilibration, the pH of the composition is adjusted to about 4.5 to about 7.5 with 0.1N aqueous hydrochloric acid (HCl) and 1.0N aqueous sodium hydroxide (NaOH), and made up to volume with distilled water. Preservatives are added to the composition at any possible stage during manufacture.

[0116] Use of the composition The ophthalmic composition of the present disclosure may be for use in the treatment of ocular conditions, particularly posterior ocular conditions, typically poorly water-soluble drugs advantageously complexed with the above-mentioned cyclodextrins. In certain embodiments, the ophthalmic composition of the present disclosure may be for use in the treatment of, for example, diabetic retinopathy (including background diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema); age-related macular degeneration (AMD) (including neovascular (wet / exudative) AMD, dry AMD, and geographic atrophy); pathologic choroidal neovascularization (CNV) by any mechanism (i.e., high myopia, trauma, sickle cell disease, ocular histoplasmosis, vascular muscle, traumatic choroidal rupture, optic nerve drusen, and some retinal dystrophies); pathologic choroidal neovascularization (CNV) by any mechanism (i.e., sickle cell retinopathy, retinopathy of prematurity, Eales retinopathy, and some retinal dystrophies); The present invention may be for use in the treatment of pathological conditions caused by or exacerbated by ocular neovascularization and vascular leakage, such as in ocular neovascularization due to ocular ischemia syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic obliterative arteritis, bird's eye chorioretinopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis; uveitis; retinal vein occlusion (central or branch); ocular trauma; surgery-induced oedema; surgery-induced neovascularization; cystoid macular oedema; ocular ischemia; retinopathy of prematurity; Coats' disease; sickle cell retinopathy and / or neovascular glaucoma.

[0117] Ophthalmic compositions, more specifically compositions comprising a dexamethasone / cyclodextrin complex, including the preferred embodiments in the next section, can be used for the treatment of macular edema, such as diabetic macular edema. In this case, the ophthalmic composition can be administered topically to the eye three times a day in the amount of one drop of composition. The amount of active pharmaceutical ingredient (e.g., dexamethasone) in the composition can be 0.5% (w / v) to 5% (w / v), preferably 1% (w / v) to 4% (w / v), more preferably 1.0% (w / v) to 3.0% (w / v), by weight of active pharmaceutical ingredient based on the volume of the composition.

[0118] In other embodiments, the ophthalmic compositions of the present disclosure may be for use in treating pre-ocular conditions. The ophthalmic compositions, more specifically compositions comprising a dexamethasone / cyclodextrin complex, including the preferred embodiments in the next section, may be used for inflammation following ophthalmic surgery, typically following cataract surgery.

[0119] The present disclosure further relates to a method of treating an eye disorder comprising topically administering to the eye, for example using a multi-dose eye dropper, a therapeutically effective amount of the aqueous ophthalmic composition described herein.

[0120] The present disclosure also provides the use of an aqueous ophthalmic composition as described herein in the manufacture of a medicament for the treatment of an ocular disorder, particularly in the manufacture of a multi-dose pharmaceutical dosage form for the treatment of an ocular disorder.

[0121] The compositions of the present disclosure do not need to be administered as frequently as known topical compositions.In fact, the high concentration and long delivery time of the active pharmaceutical ingredient in the composition significantly increases the bioavailability of the active pharmaceutical ingredient in the posterior segments, thereby allowing for less frequent administration and improving patient compliance.

[0122] The present disclosure is also directed to the use of the compositions as ophthalmic microsuspensions, particularly multi-dose ophthalmic microsuspensions, so that depending on the indication and its severity, the solution can be administered instead of or in addition to ophthalmic injection solutions, respectively, thereby significantly increasing patient compliance and clinical outcomes.

[0123] Preferred Embodiments In a particularly preferred embodiment, the aqueous composition comprises: 1% to 4% dexamethasone, e.g. 1.5% to 3% dexamethasone; 1% to 35% gamma-cyclodextrin, for example 5% to 25% gamma-cyclodextrin; 2.2% to 2.8% polymer, or 2.8% to 3.2%, e.g. 2.5% or 3.0%, of a polymer, typically a poloxamer; 0% to 0.2% of a stabilizer, e.g. 0.1% of a stabilizer, typically edetate disodium; 0% to 0.5% of an additive that prevents oxidation of the corticosteroid, e.g., 0.2% to 0.4%, or 0.2% to 0.3% of an additive that prevents oxidation of the corticosteroid, typically a phenolic antioxidant or a reducing agent (such as a water-soluble natural antioxidant), e.g., sodium thiosulfate, L-methionine, or 3,4-dihydroxybenzoic acid; 0% to 1% isotonicity agent, e.g., 0.57% electrolyte, typically sodium chloride; and water; Here, the percentages are weight percentages based on the volume of the composition.

[0124] In certain embodiments, the aqueous composition comprises or consists essentially of: 1% to 4% dexamethasone, for example 1.5% to 3% dexamethasone; 1% to 35% gamma-cyclodextrin, for example 5% to 25% gamma-cyclodextrin; 0% to 0.2% of a stabilizer, e.g. 0.1% of a stabilizer, typically edetate disodium; 0% to 1% isotonicity agent, e.g., 0.57% electrolyte, typically sodium chloride; and water; Here, the percentages are weight percentages based on the volume of the composition.

[0125] In certain embodiments, the aqueous compositions for use described herein comprise or consist essentially of: 1% to 4% dexamethasone, e.g. 1.5% to 3% dexamethasone; 1% to 35% gamma-cyclodextrin, for example 5% to 25% gamma-cyclodextrin; Optionally 2.2% to 2.8% polymer, or 2.8% to 3.2% polymer, e.g. 2.5% or 3.0% polymer, typically a poloxamer; 0% to 0.2% of a stabilizer, e.g. 0.1% of a stabilizer, typically edetate disodium; an additive to prevent oxidation of the dexamethasone at 0% to 0.8%, for example 0.1% to 0.5%, or 0.2% to 0.4%, an additive to prevent oxidation of the corticosteroid, typically a phenolic antioxidant or reducing agent (such as a water-soluble natural antioxidant), for example sodium thiosulfate, L-methionine, or 3,4-dihydroxybenzoic acid; 0% to 1% isotonicity agent, e.g., 0.57% electrolyte, typically sodium chloride; and water; Here, the percentages are weight percentages based on the volume of the composition.

[0126] More specifically, particularly preferred embodiments are eye drops comprising or consisting essentially of: 1.5% dexamethasone; 14% gamma-cyclodextrin; 2.5% poloxamer; 0% to 0.2% of a stabilizer, e.g., 0.1% edetate disodium; 0%-1% isotonicity agent, e.g. 0.57% sodium chloride; 0% to 0.6% of an additive to prevent oxidation of the dexamethasone, for example 0.2% to 0.4% of an additive to prevent oxidation of the corticosteroid, typically a phenolic antioxidant or a reducing agent (such as a water-soluble natural antioxidant), for example sodium thiosulfate, L-methionine, or 3,4-dihydroxybenzoic acid; and, water; Here, the percentages are weight percentages based on the volume of the composition.

[0127] Typically, eye drops have the following ingredients: 1.5% dexamethasone; 14% gamma-cyclodextrin; 2.5% poloxamer; 0.0% to 0.1% edetate disodium; 0.57% sodium chloride; 0.0% to 0.5% sodium thiosulfate; and water.

[0128] Another particular embodiment is an eye drop comprising or consisting essentially of: 3% dexamethasone; 1% to 35% gamma-cyclodextrin, for example 20% to 25% gamma-cyclodextrin; optionally 2.8% to 3.2% polymer, e.g. 3.0% polymer, typically a poloxamer; 0% to 0.2% of a stabilizer, e.g. 0.1% of a stabilizer, typically edetate disodium; an additive to prevent oxidation of the dexamethasone at 0% to 0.6%, for example 0.1% to 0.5%, or 0.2% to 0.4%, an additive to prevent oxidation of the corticosteroid, typically a phenolic antioxidant or reducing agent (such as a water-soluble natural antioxidant), for example sodium thiosulfate, L-methionine, or 3,4-dihydroxybenzoic acid; 0% to 1% isotonicity agent, e.g., 0.57% electrolyte, typically sodium chloride; and water; Here, the percentages are weight percentages based on the volume of the composition.

[0129] Another particular embodiment is an eye drop comprising or consisting essentially of: 3% dexamethasone; 20%-25% gamma-cyclodextrin; Optionally 2.8% to 3.2% poloxamer; e.g. 3.0% poloxamer; 0% to 0.2% of a stabilizer, e.g., 0.1% edetate disodium; 0%-1% isotonicity agent, e.g. 0.57% sodium chloride; an additive to prevent oxidation of the dexamethasone at 0% to 0.6%, for example 0.1% to 0.5%, or 0.2% to 0.4%, an additive to prevent oxidation of the corticosteroid, typically a phenolic antioxidant or reducing agent (such as a water-soluble natural antioxidant), for example sodium thiosulfate, L-methionine, or 3,4-dihydroxybenzoic acid; and, water; Here, the percentages are weight percentages based on the volume of the composition.

[0130] Eye drops typically contain the following ingredients: 3% dexamethasone; 20% to 25% gamma-cyclodextrin; e.g. 23% gamma-cyclodextrin; 2.8% to 3.2% poloxamer; 0.1% edetate disodium; 0.57% sodium chloride; and 0.0% to 0.5% sodium thiosulfate; typically 0% sodium thiosulfate, and water.

[0131] In a preferred embodiment of the method, the eye drops for use in the method comprise or consist essentially of: 1.5% dexamethasone; 14% gamma-cyclodextrin; 2.5% poloxamer; 0% to 0.2% of a stabilizer, e.g., 0.1% edetate disodium; 0%-1% isotonicity agent, e.g. 0.57% sodium chloride; 0% to 0.6% of an additive to prevent oxidation of the dexamethasone, for example 0.1% to 0.5%, or 0.2% to 0.4% of an additive to prevent oxidation of the corticosteroid, typically sodium thiosulfate; and, water; Here, the percentages are weight percentages based on the volume of the composition.

[0132] The above composition embodiments are further characterized in that said composition has a final pH of 4.0 to 6.0, preferably 4.3 to 5.7, and more preferably 4.5 to 5.5.

[0133]

[0033] The above composition embodiments are further characterized in that the amount of sorbic acid or a salt thereof in the composition may be from 0.01% (w / v) to 5% (w / v), in particular from 0.1% (w / v) to 2% (w / v), preferably from 0.2% (w / v) to 1% (w / v), more preferably from 0.2% (w / v) to 0.8% (w / v), expressed as weight of sorbic acid or sorbate relative to the volume of the composition.

[0134] Also, the composition contains only sorbic acid or a sorbate salt as a preservative. No additional antimicrobial preservative is added. Thus, the antimicrobial preservative used in the aqueous composition of the present disclosure consists essentially of sorbic acid or a sorbate salt. In some embodiments, the preservative consists essentially of sorbic acid or a sorbate salt.

[0135] The antimicrobial preservative does not include a conventional topical ophthalmic antimicrobial agent selected from the group consisting of benzalkonium chloride, benzethonium chloride, butyl-para-hydroxybenzoate, chlorobutanol, methyl-para-hydroxybenzoate, polyguaternium-1, propyl-para-hydroxybenzoate, or an oxidizing antimicrobial preservative including perborate, zinc or chlorite ions.

[0136] The aqueous composition of the present disclosure is preferably contained in a multi-dose eye dropper container. A conventional three-piece eye dropper container is made of three plastic parts assembled to ensure the airtightness of the bottle, namely a bottle or core container, a tip or eye dropper that allows the liquid to be dispensed as drops, and a screw-on cap that allows the entire container system to be opened and closed. The entire system is usually made of polyolefin-based thermoplastic materials with different densities, preferably using LDPE (low density polyethylene) for both the container and the dropper. Before the first opening of the container system, the container allows the product integrity, including sterility, to be preserved. After the first opening of the container, the prevention of microbial contamination of the liquid formulation is guaranteed for a period of about four weeks by the presence of an antimicrobial preservative in the composition.

[0137] In certain embodiments, the multi-dose eye drop containers of the present disclosure have a total volume of 1 ml, 2 ml, 5 ml, or 10 ml. The bottles can be partially filled or filled to a maximum total volume to accommodate up to a one-month supply of therapeutic treatment.

[0138] The multi-dose eye dropper container comprises an aqueous composition of the present disclosure, preferably an aqueous composition of the preferred embodiments described above.

[0139] Embodiment Item 1. An aqueous composition comprising: a drug / cyclodextrin complex comprising a drug and α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin; and An antimicrobial preservative comprising, or consisting essentially of, sorbic acid or a pharma- ceutically acceptable sorbate salt.

[0140] Item 2. The aqueous composition according to item 1, wherein the drug is selected from the group consisting of ace inhibitors, kinase inhibitors, drugs affecting basement membranes, drugs affecting endothelial cell proliferation, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergic drugs, anti-inflammatory drugs, steroidal anti-inflammatory drugs, antihypertensive drugs, antibacterial drugs, antiviral drugs, antifungal drugs, antiparasitic drugs, antiglaucoma drugs, ocular hypotensive drugs, prostaglandin analogs, anti-infective drugs, antitumor drugs, antimetabolites, and angiogenesis inhibitors, chloride channel activators, small molecule inhibitors of NLRP3 inflammasome for the treatment of inflammatory diseases, MCC-950, echothiopate iodine, and atropine, preferably dexamethasone.

[0141] Item 3. The aqueous composition according to item 1 or 2, wherein the cyclodextrin is γ-cyclodextrin, preferably natural γ-cyclodextrin.

[0142] Item 4. The aqueous composition according to any one of Items 1 to 3, wherein the pharma- ceutically acceptable sorbate is selected from the group consisting of potassium sorbate, sodium sorbate, and calcium sorbate.

[0143] Item 5. The aqueous composition according to any one of Items 1 to 4, wherein the sorbic acid or the pharma- ceutically acceptable sorbate is contained at a concentration of 0.01% (w / v) to 5% (w / v), preferably 0.1% (w / v) to 2% (w / v), more preferably 0.2% (w / v) to 1% (w / v), and even more preferably 0.2% (w / v) to 0.8% (w / v), by weight of the sorbic acid or the sorbate based on the volume of the composition.

[0144] Item 6. The aqueous composition according to any one of Items 1 to 5, wherein the α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin is contained in an amount of 1% (w / v) to 35% (w / v), preferably 5% (w / v) to 30% (w / v), and more preferably 10% (w / v) to 25% (w / v), by weight of cyclodextrin based on the volume of the composition.

[0145] Item 7. The aqueous composition according to any one of Items 1 to 6, which is a microsuspension comprising particles of the drug / cyclodextrin complex, wherein from about 5% (w / v) to about 40% (w / v), preferably 10% (w / v) to 30% (w / v) of the drug is in solution as dissolved free drug or as dissolved drug / cyclodextrin complex, and from about 60% (w / v) to about 95% (w / v), preferably 70% (w / v) to 90% (w / v) by weight of the drug is in solid drug / cyclodextrin complex particles.

[0146] Item 8. A microsuspension comprising particles of the drug / cyclodextrin complex, wherein the particles in the solid phase have an average size D 50 The aqueous composition according to any one of items 1 to 7, wherein the average particle size is from about 1 μm to about 100 μm, typically from about 1 μm to 50 μm, more preferably from 1 to 25 μm.

[0147] Item 9. The aqueous composition according to any one of Items 1 to 8, further comprising a chelating agent as a stabilizer at 0.01% (w / v) to 5% (w / v), preferably 0.05% (w / v) to 3% (w / v), more preferably 0.07% (w / v) to 2.5% (w / v), and even more preferably 0.1% (w / v) to 2% (w / v).

[0148] Item 10. The aqueous composition according to item 9, wherein the chelating agent is a dicarboxylic acid or a polycarboxylic acid.

[0149] Item 11. The aqueous composition according to item 10, wherein the chelating agent is selected from the group consisting of ethylenediamine-tetraacetic acid (EDTA), 2,2',2''-nitrilotriacetic acid (NTA), malic acid, maleic acid, succinic acid, and citric acid, and is preferably EDTA.

[0150] Item 12. The aqueous composition according to any one of Items 1 to 11, having a pH in the range of 3.5 to 9, preferably 4.0 to 6.5, and more preferably 5.0 to 6.0.

[0151] Item 13. The aqueous composition according to any one of Items 1 to 11, wherein the drug is dexamethasone, and wherein the pH is in the range of 4 to 6, preferably 4.5 to 5.7, and more preferably 4.5 to 5.5.

[0152] Item 14. The aqueous composition according to any one of Items 1 to 13, wherein the composition comprises a water-soluble polymer in an amount of from about 0.1% (w / v) to 5% (w / v), preferably 0.3% (w / v) to 3% (w / v), more preferably 0.5% (w / v) to 2% (w / v).

[0153] Item 15. The aqueous composition according to any one of items 1 to 14, further comprising the presence of one or more surface-active polymers selected from the group consisting of poloxamer, tyloxapol, polyalkylene glycol, hydroxyalkylcellulose, hydroxyalkylalkylcellulose, and polyvinyl alcohol.

[0154] Item 16. The aqueous composition according to any one of Items 1 to 15, further comprising an isotonicity agent.

[0155] Item 17. The aqueous composition of item 16, wherein the tonicity agent comprises sodium chloride.

[0156] Item 18. The aqueous composition according to Item 17, wherein the composition contains sodium chloride in an amount of 0.01% (w / v) to 0.09% (w / v), preferably 0.1% (w / v) to 0.7% (w / v), more preferably 0.3% (w / v) to 0.7% (w / v).

[0157] Item 19. The aqueous composition according to any one of Items 1 to 18, wherein the aqueous composition does not contain any other antimicrobial preservatives.

[0158] Item 20. The aqueous composition according to any one of Items 1 to 19, wherein the aqueous composition does not contain a topical ophthalmic antibacterial agent selected from the group consisting of benzalkonium chloride, benzethonium chloride, butyl-para-hydroxybenzoate, chlorobutanol, methyl-para-hydroxybenzoate, polyguaternium-1, propyl-para-hydroxybenzoate, or an oxidizing antibacterial preservative comprising a perborate ion, a zinc ion, or a chlorite ion.

[0159] Item 21. Comprising or consisting essentially of: 1% to 4% dexamethasone; e.g. 1.5% or 3% dexamethasone, 1% to 35% gamma-cyclodextrin, for example 5% to 25% gamma-cyclodextrin; 0.01% by weight (w / v) to 5% by weight (w / v), preferably 0.1% by weight (w / v) to 2% by weight (w / v), more preferably 0.2% by weight (w / v) to 1% by weight (w / v) of sorbic acid or a sorbate salt; optionally 2.2% to 2.8% polymer, or 2.8% to 3.2% polymer, for example 2.5% or 3.0% polymer, typically a poloxamer, preferably poloxamer 407; 0% to 0.2% of a stabilizer, e.g. 0.1% of a stabilizer, typically edetate disodium; 0% to 0.8% of an additive to prevent oxidation of said dexamethasone, for example 0.1% to 0.5%, or 0.2% to 0.4%, of an additive to prevent oxidation of the corticosteroid, typically a phenolic antioxidant or reducing agent (such as a water-soluble natural antioxidant), more preferably sodium thiosulfate; 0% to 1% isotonicity agent, e.g. 0.57% electrolyte, typically sodium chloride; The pH is in the range of 4.5 to 5.5; and water; 21. The aqueous composition according to any one of items 1 to 20, wherein the percentages are weight percentages based on the volume of the composition.

[0160] Item 22. The aqueous composition according to item 21, which is a suspension comprising a solid complex of dexamethasone and gamma-cyclodextrin.

[0161] Item 23. The aqueous composition according to any of items 21 or 22, which is a microsuspension and preferably comprises 80% to 95% of said corticosteroid in microparticles having a diameter of 1 μm to 10 μm.

[0162] Item 24. The aqueous composition according to any of Items 1 to 23, which is a multi-dose ophthalmic composition.

[0163] Item 25. A multi-dose eye drop container, preferably having a volume comprised between 2 mL and 10 mL, more preferably between 2.5 mL and 5 mL, containing the aqueous composition according to any one of items 1 to 24.

[0164] Item 26. The aqueous composition according to any of Items 1 to 24 for use in the topical treatment of a retinal disease.

[0165] Item 27. The aqueous composition according to any of items 1 to 25 for use in treating a condition of the posterior and / or anterior segment of the eye.

[0166] Item 28. The aqueous composition for use according to Item 26, wherein the condition is selected from the group consisting of age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), retinopathy of prematurity, pathological choroidal neovascularization (CNV), and inflammation after ophthalmic surgery (typically after cataract surgery).

[0167] Item 29. A method for treating a condition of the posterior and / or anterior segments of the eye in a subject in need thereof, the method comprising a step of topically applying to the ocular surface of the subject an aqueous composition according to any one of items 1 to 24, comprising a drug as an active principle, in an amount that delivers a therapeutically effective amount of the drug to the segment or segments of the eye.

[0168] Item 30. A method for avoiding microbial contamination of an eye drop comprising cyclodextrin, the method comprising adding an antimicrobial preservative effective amount of sorbic acid or a pharma-ceutically acceptable salt thereof to the eye drop.

[0169] Item 31. The method according to item 30, wherein the eye drops are contained in a multi-dose eye dropper, preferably made of polyolefin thermoplastic materials of different densities, preferably LDPE.

[0170] Item 32. A method for producing an eye drop containing cyclodextrin, the method comprising the steps of: (i) preparing a cyclodextrin-containing eye drop; and (ii) preparing a cyclodextrin-containing eye drop. (i) providing an eye drop comprising a drug / cyclodextrin complex comprising an α-cyclodextrin, a β-cyclodextrin or a γ-cyclodextrin; and (ii) adding to the eye drop an amount of sorbic acid or a pharma- ceutically acceptable salt thereof effective as an antimicrobial preservative.

[0171] [Example] In view of the foregoing description and the following examples, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The examples provided should not be considered exhaustive, but merely illustrative of only a few of the many embodiments contemplated by the present invention.

[0172] [Measurement method] Particle size diameter D 50 The diameter D of particles such as a solid complex of an active pharmaceutical ingredient and cyclodextrin 50 is also known as the median or medium value of the particle size distribution. 50 corresponds to the particle diameter value at 50% of the cumulative distribution. For example, D 50 If the diameter D is 5 μm, then 50% of the particles in the sample are larger than 5 μm and 50% are smaller than 5 μm. 50 is usually used to represent the particle size of a particle group.

[0173] Diameter D 50 The particle size of the complex containing the active pharmaceutical ingredient is determined by laser diffraction particle size analysis, applying the following parameters according to Pharm. Eur. 2.9.31 (Particle size analysis by laser diffraction, Jan 2010):

[0174] [Table 2]

[0175] Analysis of the samples with an Olympus BX43 light microscope was according to Pharm.Eur.2.9.37. 1 μl of the manually homogenized eye drops was scanned at different magnifications (up to 40x). Processing of the photomicrographs was performed with an Olympus LC30 digital camera and LCmicro v2.2 software.

[0176] Percentage of drug in solid complex and percent of drug dissolved The amount of drug in the form of a solid complex and the amount of dissolved drug are obtained by centrifuging the composition at 6000 rpm at a temperature of 22-23°C for 20-30 minutes.

[0177] The amount of dissolved drug corresponds to the amount of drug in the supernatant as determined by high performance liquid chromatography.

[0178] The percentage of drug in the form of a solid complex is calculated by the following formula:

[0179]

number

[0180] Where: "Total Drug" is the total amount of drug introduced into the composition in mg / mL; and "Dissolved drug" is the amount of drug in the supernatant expressed as mg / mL.

[0181] The percentage of drug dissolved is calculated using the following formula: % drug dissolved = 100 - % drug in solid complex.

[0182] Example 1: Screening of antimicrobial preservative systems Several antimicrobial preservatives commonly used and approved for topical ophthalmic drugs from a regulatory perspective were tested head-to-head against an ophthalmic suspension of dexamethasone containing native γ-cyclodextrin. Because the pH of the formulation can affect the effectiveness of the antimicrobial activity, all samples were set at the formulation's target pH of pH 5.0 to ensure maximum stability.

[0183] The concentration of each evaluated preservative is set to the maximum limit acceptable from a regulatory point of view according to the US-FDA database ("Inactive Ingredients List").

[0184] [Table 3]

[0185] [Table 4]

[0186] Methodology for Antimicrobial Preservative Effectiveness: For the evaluation of antimicrobial preservatives, antimicrobial activity tests (AET) are performed according to both USP-NF and EP standards.

[0187] USP-NF: "United States Pharmacopeia" Monographs <51> EP: "European Pharmacopoeia" monograph <50103> .

[0188] These AETs consist of testing drug formulations containing a concentration of antimicrobial preservative with specific microbial strains. Results are provided in microbial reduction expressed in logarithmic units. Pass criteria are specific to each standard (either US or EU) according to the table below. All criteria must be achieved over a 28 day period in order to declare the test passed. If at least one criterion is not met, the entire test is failed.

[0189] [Table 5] JPEG2025505557000008.jpg34169

[0190] Based on current knowledge, these three microbial challenge tests (AET), also known in the past as preservative effectiveness tests (PET), are known to be more or less difficult to pass. The EP / A test is known to be the most difficult test to pass. EB / B is less difficult than EB / A. The USP-NF test is usually less difficult than EP / B or in some cases is as difficult.

[0191] [Table 6]

[0192] From the examples it can be concluded that none of the antibacterial agents tested were effective in dexamethasone formulations containing gamma-cyclodextrin, with the exception of the sorbic acid derivatives: sorbic acid and potassium sorbate.

[0193] The sorbic acid derivative in the preparation of this example meets the USP-NF AET acceptance criteria but does not meet the EP standard acceptance criteria.

[0194] Example 2: Sorbic acid derivatives (pH 4-6) Two formulations of dexamethasone ophthalmic suspension were prepared at two different pH values, pH 4.0 and pH 6.0. Each formulation was evaluated for efficacy to compare the antimicrobial behavior of two different sorbic acid derivatives according to USP-NF methodology.

[0195] [Table 7]

[0196] From this, it can be concluded that both sorbic acid and potassium sorbate have similar antimicrobial preservative profiles with the same activity in the pH ranges tested. For both compounds, the antimicrobial activity is affected by pH. This antimicrobial activity meets USP-NF at pH below 6.0, typically 4.0-5.7, more preferably 4.5-5.5.

[0197] Example 3: Stability stress testing Example 2 shows that sorbic acid derivatives can be utilized as antimicrobial preservative systems in γ-cyclodextrin-containing ophthalmic compositions. To evaluate the stability behavior of sorbic acid derivatives in such compositions, a temperature stress test was performed on two compositions containing either sorbic acid or potassium sorbate. The test consisted of autoclaving the compositions in glass containers and subjecting them to three successive cycles of 121° C. / 20 min. Such temperature exposure is not representative of normal storage conditions for such products, but can be used to spontaneously degrade the formulation and detect any differences between the samples tested. The test also includes one “no preservative” sample as a reference point (reference sample 1).

[0198] [Table 8]

[0199] [Table 9]

[0200] Sorbic acid and potassium sorbate appear to have slightly different stability profiles in gamma-cyclodextrin formulations in glass containers at pH 5. In this particular example containing dexamethasone, potassium sorbate appears to be more stable.

[0201] The stability profile of potassium sorbate is satisfactory and meets all the acceptance criteria. It is noted that the two sorbic acid derivatives have a slight stabilizing effect on the dexamethasone used as the drug-substance in this particular example (slightly more major impurities, but less reduction in the total dexamethasone content).

[0202] From a stability standpoint, both sorbic acid and potassium sorbate can be used in gamma-cyclodextrin-containing compositions, with potassium sorbate further comprising dexamethasone being preferred for such compositions.

[0203] Example 4: Determination of the Minimum Effective Dose of Potassium Sorbate

[0204] [Table 10]

[0205] In conclusion for the above mentioned dexamethasone eye drops, the minimum effective amount of potassium sorbate used as an antimicrobial agent is 0.235% w / v (according to USP-NF AET methodology).

[0206] Example 5: Effect of some formulation excipients: The above-mentioned eye drops contain two excipients intended specifically to stabilize the dexamethasone active ingredient, namely sodium thiosulfate (STS), used as an antioxidant, and EDTA, used as a stabilizer.

[0207] EDTA is a pharmaceutical excipient known to improve the effectiveness of some antimicrobial preservatives. EDTA is not powerful enough to be considered an antimicrobial preservative by itself, but may be considered as a preservative adjuvant when used, for example, with either quaternary ammonium agents or parabens. Conversely, other antimicrobial preservatives, such as mercury derivatives including thimerosal and phenylmercuric nitrate, exhibit reduced antimicrobial preservative activity in the presence of EDTA (Handbook of Pharmaceutical excipients, 6 th Ed., Pharmaceutical Press editions, 2009, “Edetic acid” monograph).

[0208] STS and EDTA are included in the example dexamethasone formulation to specifically improve the long-term storage stability of this corticoid. However, for formulations containing active compounds other than corticoids, it would be useful to know whether these two excipients affect the antimicrobial preservative activity of the formulation.

[0209] To investigate this issue, three samples containing potassium sorbate used at the maximum permitted concentration were designed to evaluate the effects of STS and EDTA on the effectiveness of the antimicrobial preservative provided by the sorbic acid derivative.

[0210] [Table 11]

[0211] The results revealed that neither EDTA nor STS had any improving effect on the antimicrobial preservative activity of potassium sorbate. Surprisingly, the antimicrobial preservative activity of the sorbic acid derivatives is further improved in the absence of at least one of these compounds. The requirements of criterion B of the EP / AET are fulfilled, but not in the presence of these two excipients (the USP / AET criteria are fulfilled only in this case).

[0212] As a result, the formulation of liquid preparations containing drug / γ-cyclodextrin complexes can be preserved from a microbiological standpoint by sorbic acid or one of its salts. Furthermore, it is noted that the antibacterial activity of sorbic acid derivatives is inversely proportional to the dosage of either STS or EDTA. The lower the EDTA concentration in the formulation containing drug / cyclodextrin complexes, the higher the effectiveness of the antibacterial preservative of the sorbic acid derivatives. Thus, the present disclosure provides aqueous compositions that also exhibit improved antibacterial preservative activity while reducing the dosage of either STS or EDTA.

[0213] The above examples show that sorbic acid and potassium sorbate exhibit excellent antimicrobial preservative effects at low preservative concentrations for aqueous ophthalmic microsuspensions containing solid dexamethasone / cyclodextrin complex in the presence of various pharmaceutical excipients. Below are examples showing that antimicrobial preservative effects are maintained when dexamethasone is replaced with other active pharmaceutical ingredients (APIs), such as dorzolamide, everolimus, and latanoprost.

[0214] Example 6: Aqueous Dorzolamide / Cyclodextrin Microsuspension: The composition of the aqueous dorzolamide / cyclodextrin microsuspension formulation was as follows: 1.1% (w / v) dorzolamide hydrochloride (Curia, Spain), 7.0% (w / v) gamma-cyclodextrin, 0.1% (w / v) EDTA, 0.05% (w / v) tyloxapol, 0.5% (w / v) hydroxypropyl methylcellulose (Metolose 90SH-4000SR), 0.47% (w / v) potassium sorbate, hydrochloric acid QS to pH 5.0, and water (USP Type 1) QS. The pH of the final product was 4.99, and 64% of the drug was solid drug / cyclodextrin microparticles. The formulation passed the USP / NF antimicrobial activity test (AET) and failed AET-EP / A and AET-EP / B.

[0215] Example 7: Aqueous everolimus / cyclodextrin microsuspension: The composition of the aqueous everolimus / cyclodextrin microsuspension was as follows: 0.025% (w / v) everolimus (BrightGene, China), 10% (w / v) gamma-cyclodextrin, 0.1% (w / v) EDTA, 0.1% (w / v) tyloxapol, 0.47% (w / v) potassium sorbate, hydrochloric acid QS to pH 5.0, and water (USP type 1) QS. The pH of the final product was 5.01, and 62% of the drug was solid drug / cyclodextrin microparticles. The formulation passed both the USP / NF AET and EP B-tests and failed the EP AET-A test.

[0216] Example 8: Aqueous Latanoprost / Cyclodextrin Microsuspension: The composition of the aqueous latanoprost / cyclodextrin microsuspension was as follows: 0.005% (w / v) latanoprost (Chemodex Ltd, Switzerland), 1.6% (w / v) gamma-cyclodextrin, 0.1% (w / v) EDTA, 0.1% (w / v), 0.25% (w / v) hydroxypropyl methylcellulose (Metolose 90SH-4000SR), 0.5% (w / v) sodium chloride, 0.47% (w / v) potassium sorbate, hydrochloric acid QS to pH 5.0, and water (USP type 1) QS. The pH of the final product was 5.00, and 8% of the drug was solid drug / cyclodextrin microparticles. This formulation passed both the USP / NF AET and EP B-tests and failed the EP AET A-test.

Claims

1. An aqueous composition comprising: a drug / cyclodextrin complex comprising a drug and α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin; and An antimicrobial preservative comprising, or consisting essentially of, sorbic acid or a pharma- ceutically acceptable sorbate salt.

2. 2. The aqueous composition of claim 1, wherein the drug is selected from the group consisting of ace inhibitors, kinase inhibitors, vanilloid receptor (TRPV1) antagonists, agents affecting basement membrane, agents affecting endothelial cell proliferation, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergic agents, anti-inflammatory agents, steroidal anti-inflammatory agents, antihypertensive agents, antibacterial agents, antiviral agents, antifungal agents, antiparasitic agents, antiglaucoma agents, ocular hypotensive agents, prostaglandin analogs, anti-infective agents, antitumor agents, antimetabolites, and angiogenesis inhibitors, chloride channel activators, NLRP3 inflammasome small molecule inhibitors for the treatment of inflammatory diseases, MCC-950, echothiopate iodine, and atropine, preferably dexamethasone.

3. 3. The aqueous composition according to claim 1, wherein the cyclodextrin is a γ-cyclodextrin, preferably a natural γ-cyclodextrin.

4. The aqueous composition according to any one of claims 1 to 3, wherein the pharma- ceutically acceptable sorbate is selected from the group consisting of potassium sorbate, sodium sorbate and calcium sorbate.

5. 5. The aqueous composition according to claim 1, wherein the sorbic acid or pharma- ceutically acceptable sorbate is present in a concentration of 0.01% (w / v) to 5% (w / v), preferably 0.1% (w / v) to 2% (w / v), more preferably 0.2% (w / v) to 1% (w / v), and even more preferably 0.2% (w / v) to 0.8% (w / v), by weight of the sorbic acid or sorbate based on the volume of the composition.

6. The aqueous composition according to any one of claims 1 to 5, wherein the pH of the composition is less than 7, preferably between 4.0 and 6.5, more preferably between 5.0 and 6.0, and even more preferably between 4.5 and 5.

5.

7. 7. The aqueous composition according to any one of claims 1 to 6, wherein α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin is present in an amount of 1% (w / v) to 35% (w / v), preferably 5% (w / v) to 30% (w / v), more preferably 10% (w / v) to 25% (w / v), by weight of cyclodextrin based on the volume of the composition.

8. 8. The aqueous composition according to any one of claims 1 to 7, wherein the aqueous composition does not contain any other antimicrobial preservatives, in particular the aqueous composition does not contain a topical ophthalmic antimicrobial agent selected from the group consisting of benzalkonium chloride, benzethonium chloride, butyl-para-hydroxybenzoate, chlorobutanol, methyl-para-hydroxybenzoate, polyguaternium-1, propyl-para-hydroxybenzoate, or an oxidizing antimicrobial preservative comprising perborate, zinc or chlorite ions.

9. Aqueous composition according to any one of claims 1 to 8, comprising or consisting essentially of: 1% to 4% dexamethasone; e.g. 1.5% or 3% dexamethasone, 1% to 35% gamma-cyclodextrin, for example 5% to 25% gamma-cyclodextrin; 0.01% to 5% by weight (w / v), preferably 0.1% to 2% by weight (w / v), more preferably 0.2% to 1% by weight (w / v) of sorbic acid or a sorbate salt; Optionally 2.2% to 2.8% polymer, or 2.8% to 3.2% polymer, e.g. 2.5% or 3.0% polymer, typically a poloxamer; 0% to 0.2% of a stabilizer, for example 0.1% of a stabilizer, typically edetate disodium; 0% to 0.8% of an additive to prevent oxidation of said dexamethasone, for example 0.1% to 0.5%, or 0.2% to 0.4%, of an additive to prevent oxidation of the corticosteroid, typically a phenolic antioxidant or a reducing agent (such as a water-soluble natural antioxidant), more preferably sodium thiosulfate; 0% to 1% isotonicity agent, e.g. 0.57% electrolyte, typically sodium chloride; The pH is in the range of 4.5 to 5.5; and water; Here, the percentages are weight percentages based on the volume of the composition.

10. 10. The aqueous composition of claim 9, which is a suspension comprising a solid complex of dexamethasone and gamma-cyclodextrin.

11. The aqueous composition of any one of claims 1 to 10, which is a multi-dose ophthalmic composition.

12. A multi-dose eye dropper container comprising an aqueous composition according to any one of claims 1 to 11, preferably in a volume comprised between 2 mL and 10 mL, more preferably between 2.5 mL and 5 mL.

13. An aqueous composition according to any one of claims 1 to 11 for use in the topical treatment of a retinal disease.

14. 14. The aqueous composition for use according to claim 13, wherein the condition is selected from the group of age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), retinopathy of prematurity, pathological choroidal neovascularization (CNV), and inflammation following ophthalmic surgery (typically following cataract surgery).

15. A method for producing an eye drop containing a cyclodextrin, the method comprising the steps of: (i) providing an eye drop comprising a drug / cyclodextrin complex comprising an α-cyclodextrin, a β-cyclodextrin or a γ-cyclodextrin; and (ii) adding to the eye drop an amount of sorbic acid or a pharma- ceutically acceptable salt thereof effective as a preservative.

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