Hyaluronic acid-based formulations for the treatment and prevention of ocular hypertension and glaucoma

Abstract

To provide a stable aqueous solution of a prostaglandin analog without the need for any additives that are not naturally present in the human eye. [Solution] The present invention relates to ophthalmic compositions, including ophthalmic compositions comprising hyaluronic acid (HA) as a vehicle and one or more prostaglandin analogs, such as latanoprost, as active pharmaceutical ingredients (APIs), in combination, wherein the HA acts as a transporter for the prostaglandin analogs to the eye. The present invention also relates to the use of such ophthalmic compositions for reducing intraocular pressure to treat, prevent, and / or delay the onset or recurrence of ocular hypertension or glaucoma. The ophthalmic compositions of the present invention have improved stability, improved API solubility, and improved intraocular pressure-reducing effect.

Description

[Technical Field]

[0001] The present invention relates to ophthalmic compositions comprising a combination of hyaluronic acid (HA) as a transport vehicle and one or more prostaglandin analogs such as latanoprost as a pharmacokinetic agent (API); and the use thereof for lowering intraocular pressure to treat or prevent ocular hypertension and glaucoma. The ophthalmic compositions of the present invention have improved stability, improved API solubility, and improved intraocular pressure lowering effect. [Background technology]

[0002] This application claims the interests of U.S. Provisional Patent Application No. 63 / 041937, filed on 21 June 2020, and the entire disclosure thereof, including all figures, tables, diffusion sequences, amino acid sequences, or drawings, is incorporated herein by reference.

[0003] Eye drops for the topical treatment of ocular hypertension and glaucoma consist of a pharmacologically active pharmaceutical ingredient (API) dissolved or suspended in a vehicle. Potential functions of the vehicle include dissolving or suspending the API, stabilizing the solution during storage and patient use of the eye drops, extending the contact time between the API and the ocular surface, supporting the penetration of the API into the ocular surface, and enhancing the biocompatibility of the eye drops [Non-Patent Literature 1, 2].

[0004] Most eye drops are aqueous solutions that require additives, particularly surfactants, to dissolve lipophilic APIs. Eye drops must be sterile, which can be achieved during patient use by disposable containers (single-dose), bottles with specific dispensers to prevent microbial contamination, or the addition of preservatives such as benzalkonium chloride. Contact time with the ocular surface can be extended by adding polymers that increase the viscosity of the solution. Furthermore, mucosal adhesive additives such as hyaluronic acid can adhere to the glycocalyx of apical epithelial cells, thereby facilitating contact between the API and the ocular surface. Penetration enhancers weaken the transcellular or paracellular epithelial barrier function, thereby promoting the diffusion of APIs to the ocular surface. Salts are added to adjust osmotic pressure, and buffers are added to adjust and stabilize the pH value of the eye drops to physiological levels and to stabilize the eye drops.

[0005] Surfactants can replace cell-bound mucins in the glycocalyx of apical epithelial cells, incorporating them into the lipid bilayer that forms the cell membrane, thereby weakening the cell barrier function and supporting the transport of APIs into cells across the cell membrane [Non-Patent Literature 3, 4]. Surfactants such as benzalkonium chloride (BAK, cetalkonium chloride) and cationic polymers called polyquaternium are still widely used in ophthalmic drugs because they have a combined effect of dissolving APIs in aqueous solutions, increasing the penetration of APIs into the ocular surface, and simultaneously protecting the solution from microbial growth. These advantages come at the cost of local irritation and disastrous long-term ocular surface disease [Non-Patent Literature 5, 6].

[0006] Additives such as sodium ethylenediaminetetraacetate (EDTA) break down tight junctions between epithelial cells, leading to the formation of Ca 2+ It deprives cells of ions, thereby weakening the paracellular barrier function of the epithelium.

[0007] APIs currently available for the treatment of ocular hypertension and glaucoma belong to several pharmacological classes, including beta-blockers (timolol maleate, carteolol, betaxolol), cholinergics, carbonic anhydrase inhibitors (dorzolamide, brinzolamide), or adrenergic receptor blockers (brimonidine). The mechanisms of action of such APIs include inhibiting aqueous humor inflow, promoting aqueous humor outflow, protecting the optic nerve, and manipulating osmotic pressure between plasma and the eye. These therapies are usually administered as eye drops.

[0008] Prostaglandin inhibitors (e.g., latanoprost, unoprostone, travoprost, bimatoprost, tafluprost, etc.) lower intraocular pressure (IOP) primarily by increasing aqueous humor drainage via the uveoscleral outflow pathway.

[0009] Current eye drops for the treatment of ocular hypertension and glaucoma, containing prostaglandin analogs, can cause serious side effects in a significant percentage of patients. These ocular side effects are caused not only by the API but also, in large part, by the vehicle used. In clinical trials for regulatory approval and insurance reimbursement, the safety and performance of new topical ophthalmic drugs are often tested in comparison to the vehicle alone. This strategy makes it possible to eliminate the adverse effects of the vehicle and enhance the effectiveness of the product.

[0010] It would be advantageous to make available ophthalmic compositions that can lower intraocular pressure without damaging the ocular surface or impairing its barrier function, enabling the use of lower concentrations of APIs to achieve the intended therapeutic effect, thereby reducing the inherent side effects that may be associated with APIs, and improving patient compliance. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Morrison, PW and VV Khutoryanskiy, Advances in ophthalmic drug delivery. Ther Deliv, 2014. 5(12): p. 1297-315. [Non-Patent Document 2] Moiseev, RV, et al., Penetration Enhancers in Ocular Drug Delivery. Pharmaceutics, 2019. 11(7). [Non-Patent Document 3] Kaur, IP and R. Smitha, Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug delivery. Drug Dev Ind Pharm, 2002. 28(4): p. 353-69. [Non-Patent Document 4] Patel, A., et al., Ocular drug delivery systems: An overview. World J Pharmacol, 2013. 2(2): p. 47-64. [Non-Patent Document 5] Patel, PB, et al., Ophthalmic Drug Delivery System: Challenges and Approaches. Systematic Reviews in Pharmacy, 2010. 1(2): p. 113-120. [Non-Patent Document 6] Burgalassi, S., et al., Cytotoxicity of potential ocular permeation enhancers evaluated on rabbit and human corneal epithelial cell lines. Toxicol Lett, 2001. 122(1): p. 1-8. [Non-Patent Document 7] Dogru, M., et al., Alterations of the ocular surface epithelial mucins 1, 2, 4 and the tear functions in patients with atopic keratoconjunctivitis. Clin Exp Allergy, 2006. 36(12): p. 1556-65. [Non-Patent Document 8] Dogru, M., et al., Alterations of the ocular surface epithelial MUC16 and goblet cell MUC5AC in patients with atopic keratoconjunctivitis. Allergy, 2008. 63(10): p. 1324-34. [Non-Patent Document 9] Mantelli, F. and P. Argueso, Functions of ocular surface mucins in health and disease. Curr Opin Allergy Clin Immunol, 2008. 8(5): p. 477-83. [Non-Patent Document 10] Gurny, R., et al., Design and evaluation of controlled release systems for the eye. J Controlled Release, 1987. 6: p. 367-373. [Non-Patent Document 11] Saettone, M.F., et al., Evaluation of muco-adhesive properties and in vivo activity of ophthalmic vihicles based on hyaluronic acid. Int J Pharm, 1989. 51: p. 203-212. [Non-Patent Document 12] Saettone, M.F., et al., Evaluation of high- and low-molecular-weight fractions of sodium hyaluronate and an ionic complex as adjuvants for ophthalmic vehicles containing pilocarpine. Int J Pharm, 1991. 72: p. 131-139. [Non-Patent Document 13] Brown, M.B. and S.A. Jones, Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin. J Eur Acad Dermatol Venereol, 2005. 19(3): p. 308-18. [Non-Patent Document 14] Liao, Y.H., et al., Hyaluronan: pharmaceutical characterization and drug delivery. Drug Deliv, 2005. 12(6): p. 327-42. [Non-Patent Document 15] Khan, R., B. Mahendhiran, and V. Aroulmoji, Chemistry of hyaluronic acid and its significance in drug delivery strategies: a review. Int J Pharm Sci & Res, 2013. 4(10): p. 3699-3710. [Non-Patent Document 16] Park, K. and J.R. Robinson, Bioadhesive polymers as platforms for oral-controlled drug delivery: method to study bioadhesion. Int J Pharm, 1984. 19(2): p. 107-127.

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[0012] The inventors have found that HA is not an inert thickening polymer, but rather actively contributes to the transport of bioactive agents such as drugs to the site of action. As shown in the examples, 20 micrograms of latanoprost per milliliter dissolved in the HA vehicle of the present invention is more effective in lowering intraocular pressure than 50 micrograms of latanoprost per milliliter in Xalatan® droplets, the "gold standard" containing benzalkonium chloride, which is known to transport latanoprost into the eye by weakening the ocular surface barrier. [Means for solving the problem]

[0013] The present invention provides a stable aqueous solution of prostaglandin analogs without the need for any additives that do not naturally exist in the human eye. Therefore, the ophthalmic composition is fully biocompatible, non-sensitizing, and particularly useful for long-term use as eye drops. Furthermore, the HA in the ophthalmic composition enhances the solubility of the prostaglandin analogs contained in the ophthalmic composition, as demonstrated in the example of latanoprost. [Modes for carrying out the invention]

[0014] The use of hyaluronic acid (HA) in ophthalmic drug vehicles has been suggested in non-patent literature [3, 10-16]. HA has been shown to have the effect of counteracting the irritant effects of substances on the ophthalmic epithelium [Non-patent literature 17-20]. When hyaluronic acid with three different molecular weights was examined using porcine cheek and vaginal tissue as well as a cell monolayer (Caco-2 cell line), the hyaluronic acid with the lowest molecular weight showed improved mucosal adhesion and the best penetration enhancement in each substrate tested [Non-patent literature 25].

[0015] The inventors propose that HA can deliver APIs across the ocular epithelial barrier without damaging the ocular surface or impairing its barrier function. Using HA in the drug vehicle makes it possible to achieve the intended therapeutic effect with lower concentrations of API. This further reduces the inherent side effects of the API. Eye drops containing HA as a side-effect-free vehicle have the potential to be a platform for the development of next-generation topical ophthalmic drugs for treating vision-threatening diseases. In particular, HA can replace current penetration enhancers in current eye drop formulations and significantly reduce side effects in the long-term topical treatment of ocular hypertension and glaucoma.

[0016] Healthy ocular surface epithelium is tissue-distributed and smooth. The lipid bilayer plasma membrane of apical corneal epithelial cells is woven by microplicaes lined with an anti-adhesive, water-binding, and protective glycocalyx (Wilcox MDP et al. [Non-Patent Literature 23], particularly Figure 3, originally published by Gipson IK and P Argueso [Non-Patent Literature 24]). The glycocalyx consists mainly of membrane-bound mucins and is covered by a mucous tear film with water-binding and lubricating properties due to dissolved gel-forming mucin MUC5AC, mainly secreted by conjunctival goblet cells [Non-Patent Literature 7-9]. MUC16, the largest membrane-bound mucin, extends from the apex of the microplicas into the mucous tear film, preventing cell adhesion and bacterial attachment and invasion. MUC16 plays an important role not only in the cell-epithelial barrier function but also in tight junctions between epithelial cells and, consequently, in the paracellular barrier function.

[0017] While not wishing to be constrained by theories of the mechanism of action as a transport vehicle, the inventors propose that HA, in addition to stabilizing epithelial barrier function, acting as an anti-inflammatory agent, and promoting close contact of bioactive agents (e.g., APIs) to the ocular surface, performs one or more of the following actions: binding to MUC16 in the glycocalyx of apical epithelial cells; binding to the adhesion molecule CD44 on the apical surface of corneal and conjunctival epithelium; binding to hyaluronic acid receptors for hyaluronic acid-mediated motility (RHAMM) on the apical surface of corneal and conjunctival epithelium; enabling transient cell desorption that can create pathways or "highways" that allow for cell migration and transport of bioactive agents along paracellular pathways by increasing local tissue hydration; and binding to HA receptors for endocytosis (HARE) on the apical surface of corneal and conjunctival epithelium to induce HARE-mediated endocytosis of bioactive agents into the cytoplasm of epithelial cells. Regarding the latter proposed mechanism of action, if HARE receptors are present on the surface of ocular epithelial cells, they will cause HA to be transported internally by endocytosis. This represents a novel option for transporting bioactive agents having HA molecules as vehicles across the cell membrane of epithelial cells without damaging the cell membrane.

[0018] In subjects, commercially available eye drops containing 50 μg / ml latanoprost induced a mean intraocular pressure (IOP) reduction of 3.24 mmHg, while a prototype eye drop containing 19 μg / ml latanoprost induced a mean IOP reduction of 5.87 mmHg. This finding suggests that the combination of latanoprost and high molecular weight hyaluronic acid is more effective in lowering IOP than latanoprost alone.

[0019] Combined with HA's ability to mitigate the adverse effects of corneal toxic substances [Non-Patent Documents 17-20], patients, particularly those requiring long-term topical treatment for conditions such as ocular hypertension or glaucoma, who are currently suffering from the side effects of such treatments, are expected to benefit from this new technology using HA.

[0020] The properties of hyaluronic acid (HA) in eye drops depend on chain length and concentration. While HA concentration is usually part of the final product labeling, information regarding chain length is rarely included. This makes it extremely difficult to correlate the performance of different products reported in the literature. The average chain length or molecular weight of hyaluronic acid molecules is usually determined by gel electrophoresis, size exclusion chromatography, or small-angle light scattering, or calculated from its intrinsic viscosity [η]. Only methods for determining the intrinsic viscosity of hyaluronic acid are standardized and published in the European and Japanese Pharmacopoeias [Non-Patent Literature 21, 22]. Furthermore, ultra-high molecular weight HA (i.e., 2.5 m) 3 The clinical performance of eye drops containing low molecular weight HA (1.8m³ / kg or more) is as follows: 3 (less than / kg) ~ Medium molecular weight HA (1.8m 3 / kg~2.5m 3 This differs from the clinical performance of eye drops containing less than 1 kg.

[0021] One aspect of the present invention relates to an ophthalmic composition comprising hyaluronic acid and at least one active ingredient comprising a prostaglandin analog, wherein the HA acts as a transport vehicle (transporter) for the prostaglandin analog to the eye.

[0022] In some embodiments, the ophthalmic composition contains no substances other than the above (or more) active ingredients that do not naturally exist in the human eye.

[0023] In some embodiments, the ophthalmic composition is preservative-free.

[0024] In some embodiments, the prostaglandin analog is present at a concentration lower than that which is effective in treating and / or preventing ocular hypertension or glaucoma without the HA (i.e., in the absence of the HA or the prostaglandin analog alone). In some embodiments, the prostaglandin analog is latanoprost and is present at a concentration of less than 50 micrograms per milliliter (less than 50 μg / mL). In some embodiments, the latanoprost is present at a concentration of less than 0.005% by weight relative to the total volume (w / v) of the ophthalmic composition. In some embodiments, the latanoprost is present at a concentration of less than 30 micrograms per milliliter. In some embodiments, the latanoprost is present at concentrations ranging from about 2 micrograms to about 45 micrograms per milliliter, about 10 micrograms to about 40 micrograms per milliliter, about 15 micrograms to about 25 micrograms per milliliter, or about 20 micrograms to about 25 micrograms per milliliter. In some embodiments, the latanoprost is present at a concentration of about 20 micrograms per milliliter.

[0025] The above prostaglandin analogs may be F2a analogs such as latanoprost, travoprost, bimatoprost, tafluprost, prostaglandin F2a-ethanolamide, bimatoprost (free acid)-d4, bimatoprost-d4, latanoprost ethylamide, unoprostone, and unoprostone isopropyl ester, or a combination of two or more of these. In some embodiments, at least one of the above prostaglandin analogs comprises latanoprost. Latanoprost is a prodrug (17-phenyl substituted PGF2α) of prostaglandin F2α isopropyl ester, which is hydrolyzed by corneal esterases to the biologically active latanoprost acid and proceeds to the anterior tissue (Russo A et al., Clin Ophthalmol, 2008 Dec; 2(4): 897-905).

[0026] In some embodiments, the prostaglandin analog comprises latanoprost, which is present at a concentration ranging from about 20 micrograms per milliliter to about 25 micrograms per milliliter. In some embodiments, at least one prostaglandin analog comprises latanoprost, which is present at a concentration of about 20 micrograms per milliliter.

[0027] In some embodiments, the prostaglandin analog is bimatoprost, present at a concentration of less than 100 micrograms per milliliter (less than 100 μg / mL). In some embodiments, the bimatoprost is present at a concentration of less than 90 micrograms per milliliter. In some embodiments, the bimatoprost is present at concentrations ranging from about 5 micrograms per milliliter to about 90 micrograms per milliliter, about 10 micrograms per milliliter to about 80 micrograms per milliliter, about 20 micrograms per milliliter to about 70 micrograms per milliliter, or about 20 micrograms per milliliter to about 60 micrograms per milliliter. In some embodiments, the bimatoprost is present at a concentration of 50 micrograms per milliliter.

[0028] In some embodiments, the prostaglandin analog is travoprost, present at a concentration of less than 30 micrograms per milliliter (less than 30 μg / mL). In some embodiments, the travoprost is present at a concentration of less than 25 micrograms per milliliter. In some embodiments, the travoprost is present at concentrations ranging from about 2 to about 25 micrograms per milliliter, about 3 to about 25 micrograms per milliliter, about 5 to about 20 micrograms per milliliter, or about 10 to about 15 micrograms per milliliter. In some embodiments, the travoprost is present at a concentration of about 15 micrograms per milliliter.

[0029] In some embodiments, the prostaglandin analog is tafluprost, present at a concentration of less than 15 micrograms per milliliter (less than 15 μg / mL). In some embodiments, the tafluprost is present at a concentration of less than 12 micrograms per milliliter. In some embodiments, the tafluprost is present at concentrations ranging from about 1 microgram to about 12 micrograms per milliliter, about 2 micrograms to about 10 micrograms per milliliter, about 2 micrograms to about 10 micrograms per milliliter, or about 3 micrograms to about 9 micrograms per milliliter. In some embodiments, the tafluprost is present at a concentration of about 7.5 micrograms per milliliter.

[0030] In some embodiments, the prostaglandin analog is unoprostone, present at a concentration of less than 1500 micrograms per milliliter (less than 1500 μg / mL). In some embodiments, unoprostone is present at a concentration of less than 1350 micrograms per milliliter. In some embodiments, unoprostone is present at concentrations ranging from about 50 micrograms per milliliter to about 1350 micrograms per milliliter, about 100 micrograms per milliliter to about 1200 micrograms per milliliter, about 200 micrograms per milliliter to about 1000 micrograms per milliliter, or about 250 micrograms per milliliter to about 900 micrograms per milliliter. In some embodiments, unoprostone is present at a concentration of about 750 micrograms per milliliter.

[0031] Advantageously, the ophthalmic composition is storage stable. In some embodiments, the ophthalmic composition is an aqueous solution that is stable for at least 4 weeks, at least 3 months, or at least 6 months under one or more of the following conditions: (i) a temperature of 15 to 25°C, (ii) a temperature of 2 to 8°C, or (iii) a temperature of 25°C at a relative humidity of 60%.

[0032] In some embodiments, the hyaluronic acid is at least 2.5 ml 3 It has an intrinsic viscosity of / kg. In some embodiments, the hyaluronic acid is at least 2.9m 3 It has an intrinsic viscosity of / kg.

[0033] In some embodiments, the hyaluronic acid has a molecular weight of at least $3 million tons. In some embodiments, the hyaluronic acid has a molecular weight in the range of $3 million to $4 million tons.

[0034] In some embodiments, the ophthalmic composition has one, two, three, or all four of the following properties. a) pH 5.8~8.5; b) Osmotic pressure 240-330 mosmol / kg; c) NaCl concentration of 7.6-10.5 g / l; and / or d) Phosphate concentration 1.0-1.4 mmol / l

[0035] In some embodiments, the ophthalmic composition is a colorless, transparent solution free from visible impurities.

[0036] In some embodiments, the ophthalmic composition is sterile.

[0037] In some embodiments, the hyaluronic acid exists in the form of COMFORT SHIELD® preservative-free sodium hyaluronate eye drops.

[0038] Optionally, the ophthalmic composition comprises a combination of two or more active ingredients that lower intraocular pressure. For example, the ophthalmic composition may comprise a prostaglandin analog and an additional agent that lowers intraocular pressure by a mechanism of action different from that of the prostaglandin analog. In some embodiments, the additional agent is a β - adrenergic blocker (e.g., timolol), a cholinergic agonist, a carbonic anhydrase inhibitor (e.g., dorzolamide, brinzolamide), or an adrenergic receptor blocker (e.g., brimonidine). In some embodiments, the additional agent comprises timolol (e.g., timolol maleate).

[0039] The ophthalmic composition may be formulated, for example, as an eye drop or an eye wash.

[0040] Another aspect of the present invention is a method for reducing intraocular pressure or maintaining reduced intraocular pressure, which is a method for reducing and maintaining intraocular pressure by topically administering the ophthalmic composition of the present invention to the ocular surface of an affected eye.

[0041] Another aspect of the present invention is a method for treating, preventing, or delaying the onset of ocular hypertension or glaucoma in a human subject, which is a treatment method of topically administering the ophthalmic composition of the present invention to the ocular surface of the eye of the subject.

[0042] The HA used in the ophthalmic composition and method of the present invention may be high - molecular - weight HA or "HMWHA". The HMWHA that may be used in the present invention is hyaluronic acid having an intrinsic viscosity of at least 2.5 m 3 / kg (i.e., 2.5 m 3 / kg or more) measured by the method described in European Pharmacopoeia 9.0, "Sodium Hyaluronate", page 3584 [Non - Patent Document 21]. Briefly, the intrinsic viscosity [η] is calculated using the Martin formula: Log 10 (n r -1 / c)=log 10It is calculated by linear least squares regression analysis using [η] + κ[η]c. In some embodiments, the high molecular weight hyaluronic acid is at least 2.9m 3 / kg (i.e., 2.9m 3 It has an intrinsic viscosity of 1 / kg or more.

[0043] In some embodiments, the hyaluronic acid has a concentration of less than 0.2% w / v. In some embodiments, the hyaluronic acid has a concentration of 0.1 to 0.19% w / v. In some embodiments, the hyaluronic acid has a concentration of 0.15% w / v.

[0044] In some embodiments, the HMWHA fluid has the following composition / characteristics corresponding to the composition / characteristics of COMFORT SHIELD® preservative-free sodium hyaluronate eye drops. a) pH 5.8~8.5; b) Osmotic pressure 240-330 mOsmol / kg; c) NaCl concentration of 7.6-10.5 g / l; and / or d) Phosphate concentration 1.0-1.4 mmol / l

[0045] In some embodiments, the fluid is a colorless, transparent solution free from visible impurities. The fluid is assumed to be sterile.

[0046] In some embodiments, the fluid according to the present invention is COMFORT SHIELD® preservative-free sodium hyaluronate eye drops.

[0047] In some embodiments, the HA has a molecular weight of at least $3 million tons, as calculated by Mark-Houwink's formula. In some embodiments, the HA has a molecular weight in the range of $3 million to $4 million tons, as calculated by Mark-Houwink's formula.

[0048] In some embodiments, the HA is hyaluronic acid. In some embodiments, the HA is crosslinked. In some embodiments, the HA is not crosslinked. In some embodiments, the HA is linear. In some embodiments, the HA is nonlinear (e.g., branched). In some embodiments, the HA is a derivative of hyaluronic acid, such as an ester derivative, an amide derivative, or a sulfated derivative, or a combination of two or more of these.

[0049] Optionally, the ophthalmic composition may contain one or more additional bioactive agents (in addition to the one or more prostaglandin analogs). The method may also include topically administering one or more additional bioactive agents to the ocular surface in the same composition as the prostaglandin analogs and HA, or in a composition different from the prostaglandin analogs and HA. The term "bioactive agent" refers to any substance that, when administered in an amount effective enough to affect tissue, affects a human or non-human animal subject. The bioactive agent may be any type of substance, such as a drug molecule or a biological preparation (e.g., polypeptides, carbohydrates, glycoproteins, immunoglobulins, nucleic acids), may be a natural product or artificially produced, and may act by any mechanism, such as pharmacological, immunological, or metabolic mechanisms. Examples of types of bioactive agents include substances that regulate intraocular pressure (e.g., enzyme inhibitors) and anti-angiogenic agents.

[0050] In some embodiments, the ophthalmic composition does not contain preservatives or cleansing agents such as quaternary ammonium preservatives (e.g., benzalkonium chloride (BAK) or cetalkonium chloride), chlorobutanol, disodium edetate (EDTA), polyquaternium-1 (e.g., POLYQUAD® preservative), stabilized oxidizing agents (e.g., stabilized oxychloro complex (e.g., PURITE® preservative)), ion-buffered preservatives (e.g., SOFZIA® preservative), polyhexamethylene biguanide (PHMB), sodium perborate (e.g., GENAQUA® preservative), tyloxapol, and sorbates.

[0051] In some embodiments, the ophthalmic composition is at least essentially free of mucin; or, to put it another way, the mucin concentration is less than 0.3% w / v.

[0052] The above ophthalmic composition may be administered to the ocular surface of one or both eyes of a subject by any topical administration method. For example, the above ophthalmic composition may be administered as one or more droplets from an eye dropper or other device for dispensing eye drops. The above ophthalmic composition may be self-administered or administered by a third party (e.g., a healthcare provider or helper). The dose administered to the ocular surface as a single or multiple dose varies depending on various factors, including the patient's condition and characteristics, the severity of symptoms, concomitant treatments, the frequency of treatment, and the desired effect. For example, one or more droplets (e.g., about 30 microliters each) may be administered.

[0053] Administering one, two, or three drops once to three times a day may, in some cases, be sufficient for the delivery of the prostaglandin analog, although more frequent topical co-administration may be required. Optionally, during administration, subjects may close their eyes to prevent excess droplets from flowing out, or they may use their fingers to support this. Optionally, during administration, subjects may tilt their heads back for a period of time (e.g., one minute).

[0054] A general aspect of the present invention provides a method for lowering intraocular pressure, comprising topically administering the ophthalmic composition of the present invention to the ocular surface of a subject. A more specific aspect of the present invention provides a method for treating, preventing, or delaying the onset or recurrence of ocular hypertension or glaucoma in a subject, comprising topically administering the ophthalmic composition of the present invention to the ophthalmic surface of a human or animal subject. In the method of the present invention, the presence of HA in the ophthalmic composition allows for the use of prostaglandin analogs at concentrations lower than those otherwise required for effective reduction of intraocular pressure.

[0055] In some embodiments, the ophthalmic composition is formulated, for example, as an eye drop or eye wash for topical administration to the ocular surface.

[0056] In some embodiments, the ophthalmic composition preferably further comprises (in combination with) other agents that lower intraocular pressure by a mechanism different from that of the prostaglandin analog. In some embodiments, the additional agents are pharmacological agents selected from miotics or cholinergics (e.g., pilocarpine or esserine), β-adrenergic antagonists or "β-blockers" (e.g., timolol maleate or betaxolol), α-adrenergic agonists (e.g., epinephrine or dipivefrin), carbonic anhydrase inhibitors (e.g., dorzolamide), Rho kinase inhibitors (e.g., netaludil), and prodrugs of prostaglandin F2a (e.g., latanoprost).

[0057] In some embodiments, the subjects to whom the ophthalmic composition is administered topically are children under 18 years of age (e.g., infants, adolescents, or boys). In other embodiments, the subjects are adults. In other embodiments, the subjects are 50 years of age or older.

[0058] For therapeutic embodiments in which a subject has ocular hypertension or glaucoma at the time of administration, the treatment method may include the step of identifying the subject as having ocular hypertension or glaucoma before topical administration of the ophthalmic composition. The subject may be identified by diagnosing a subject having ocular hypertension or glaucoma by one or more tests and / or diagnostic examinations. For example, glaucoma may be detected using one or more of the following: intraocular pressure measurement, ophthalmoscopic examination (examination of the optic nerve), visual field testing (a visual field test that creates a map of the subject's visual field to identify areas of visual acuity loss), gonioscopy (determining whether the angle at which the iris touches the cornea is open, wide, or narrowly closed), and corneal thickness measurement (measuring the thickness of the cornea).

[0059] Intraocular pressure (IOP) is the best measure for assessing the state of ocular hypertension or glaucoma and its changes, such as progression, stabilization, or improvement (Konstas AG et al., "Expert Opinion On Drug Safety," 2021 Apr;20(4):453-466; Kass MA et al., "JAMA Ophthalmol," 2021;139(5):558-566; and Allis K et al., "Cureus," 2020 Nov; 12(11): e11686). IOP may be measured using a Goldmann applanation tonometer, the gold standard instrument for measuring IOP.

[0060] Optionally, subjects may be monitored once or multiple times during and / or after treatment to assess the status and progression of treatment for ocular hypertension or glaucoma by comparing the results with previous results.

[0061] Optionally, the method includes the step of identifying the subject as having one or more signs or symptoms of ocular hypertension or glaucoma before administering the ophthalmic composition. For example, in the case of glaucoma, the signs and symptoms vary depending on the type and stage of the disorder. For example, in open-angle glaucoma, some signs and symptoms include patchy blind spots in the subject's lateral (peripheral) or central visual field, often appearing in both eyes, and tunnel vision in the advanced stage. In acute closed-angle glaucoma, some signs and symptoms include severe headache, eye pain, nausea and vomiting, blurred vision, halos around lights, and redness of the eyes.

[0062] Another aspect of the present invention relates to a kit that can be used to carry out the methods of the present invention described herein, namely, a method for lowering intraocular pressure or maintaining lowered intraocular pressure, and a method for treating, preventing, or delaying the onset or recurrence of ocular hypertension or glaucoma. The kit comprises an ophthalmic composition described herein and optionally one or more bioactive agents. If a bioactive agent is included, the bioactive agent may be packaged together with the ophthalmic composition in the same container, or it may be packaged separately in a different container from the ophthalmic composition. Thus, the kit may contain one or more bioactive agents in a separate container from the ophthalmic composition, or they may be together in the same container (e.g., "pre-mixed"). Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. Containers may be made of various materials such as glass or plastic.

[0063] The kit may include a delivery agent (separately or together with the fluid) that can be brought into contact with the ocular surface or other parts of the eye. For example, the kit may include particles (e.g., microparticles or nanoparticles) that are coated with the fluid and / or release the fluid onto the ocular surface.

[0064] Optionally, the kit may include a device for dispensing eye drops (e.g., an eye drop dispenser), which may or may not function as a container for the ophthalmic composition within the kit before the outer packaging of the kit is accessed (e.g., opened). That is, the eye drop dispensing device may function to contain the ophthalmic composition provided in an unaccessed (unopened) kit, or it may be empty and receive the ophthalmic composition after the kit has been accessed. Optionally, the kit may include a label or packaging insert containing, for example, printed or digital instructions relating to the use of the kit for carrying out the method of the present invention.

[0065] The kit may include a compartmentalized packaging material to accommodate one or more containers, such as vials and tubes, each container containing one of the distinct elements used in the method described herein. Examples of packaging materials for use in packaging pharmaceuticals include U.S. Patents 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, pumps, bags, vials, light-shielded airtight containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment.

[0066] The kit may include one or more additional containers, each containing one or more of various materials desirable from a commercial and user standpoint for using the compositions described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, carriers, packaging, containers, vials and / or tube labels that indicate the contents and / or instructions for use, and packaging inserts that include instructions for use.

[0067] Labels may be present on the container or associated with the container. Labels may be present on the container if the letters, numbers, or other characters forming the label are attached to, molded, or etched onto the container itself. Labels may be associated with the container if they are present, for example, as a packaging insert within a receptacle or carrier that also holds the container. Labels may be used to indicate that the contents should be used for a specific therapeutic purpose. Labels may also provide instructions for the use of the contents, such as those described herein.

[0068] In some embodiments of the kit, the ophthalmic composition may be present in a pack or dispenser device that can contain one or more unit dose forms containing the composition disclosed herein. The pack may include, for example, metal or plastic foil such as a blister pack. Instructions for administration may be attached to the pack or dispenser device.

[0069] Preparation of HMWHA fluid In some embodiments, the HA in the ophthalmic composition is an HMWHA fluid, and is at least 2.5 m 3 / kg (i.e., 2.5m 3 It has an intrinsic viscosity of 0.2% w / v or more (1 / kg or more), preferably an intrinsic viscosity of less than 0.2% w / v. In some embodiments, the hyaluronic acid is at least 2.9 m 3 / kg(2.9m 3 It has an intrinsic viscosity of 1 / kg or more.

[0070] Viscoelasticity is defined as a fluid property that possesses both viscous and elastic properties. Zero shear viscosity is determined as the steady-state shear plateau viscosity at the disappearance shear rate. For high-viscosity formulations, measurement using a controlled stress rheometer is preferred.

[0071] m 3The relationship between molecular weight in units of / kg and intrinsic viscosity [η] is given by the following Mark-Houwink equation. [η]=k·(Mrm) a (Mrm is the molecular weight of MDa, Coefficient k = 1.3327·10 -4 And, The coefficient a = 0.6691, The values ​​of k and a were found to be the most predictive.

[0072] HMWHA fluid may be prepared by sterilizing the filling line; adding purified water or water for injection (WFI) to a stainless steel mixing tank; adding salt while mixing; slowly adding HA and mixing until a homogeneous solution / fluid is obtained; optionally adding one or more bioactive agents such as prostaglandin analogs; adjusting the pH value by adding NaOH or HCl while continuing the mixing process as needed; transferring the solution to a sterile holding tank through a filter cartridge with a 1 μm pore size; and aseptically filling the solution into a sterile primary package (single dose or vial) by sterile filtration. In the case of a single dose, this may be done by a blow-fill-seal (BFS) process.

[0073] Preferably, the HMWHA fluid is at least essentially mucin-free, or in other words, has a mucin concentration of less than 0.3% w / v. This means that the fluid behavior or fluid properties are essentially obtained or regulated by hyaluronic acid, rather than by mucin, which is naturally present in the subject's tears and is primarily involved in its fluid behavior.

[0074] If substances that increase viscosity are added, they are preferably added toward, during, or as the final step. Mixing is carried out to obtain a homogeneous mixture. Alternatively, or in addition thereto, it is preferable to first provide purified water or water for injection as a base, and then optionally add electrolytes, buffers, and substances that do not increase viscosity to the purified water or water for injection first.

[0075] HA is further described in the monograph "Sodium Hyaluronate" on page 3583 of the European Pharmacopoeia 9.0, which is incorporated herein by reference in its entirety.

[0076] In one embodiment, the fluid used in the ophthalmic drug delivery system (ODS), method, and kit of the present invention has the characteristics listed in Table 1.

[0077] Table 1 [Table 1]

[0078] definition In the context of this invention (particularly in the context of the claims), the terms “a,” “an,” “the,” and similar terms should be interpreted as encompassing both singular and plural unless otherwise indicated herein or unless the context clearly contradicts this. Thus, for example, references to “cells” or “bioactive agents” should be interpreted as encompassing both a single cell or a single bioactive agent and multiple cells or multiple bioactive agents unless otherwise indicated or unless the context clearly contradicts this. Similarly, the term “or” is intended to include “and” unless the context clearly indicates otherwise. The abbreviation “eg” derives from the Latin “exempli gratia” and is used herein to indicate a non-restrictive example. Therefore, the abbreviation “eg” is synonymous with the term “for example.”

[0079] In the context of the present invention, the term "co-administration" refers to the topical administration of an ophthalmic composition and one or more other bioactive agents to the ocular surface, either simultaneously or sequentially in the same composition or in separate compositions.

[0080] In the context of the administration fluid of this invention, the term "effective amount" means the amount of fluid required to obtain the desired result, for example, the amount required to deliver the bioactive agent to the eye.

[0081] When used as a modifier for a composition, the term "isolated" means that the composition is produced by human intervention or isolated from its naturally occurring in vivo environment. Generally, such isolated compositions substantially contain none of the one or more materials that they normally associate with in nature, such as one or more proteins, nucleic acids, lipids, carbohydrates, or cell membranes. A "substantially pure" molecule can be combined with one or more other molecules. Therefore, the term "substantially pure" does not exclude combinations of compositions. Substantially pure may be at least about 60% by mass of the molecule. Alternatively, purity may be about 70% or 80% or higher, or even higher, for example, 90% or higher. Purity can be determined by any suitable method, including, for example, UV spectroscopy, chromatography (e.g., high-performance liquid chromatography (HPLC), gas phase), gel electrophoresis (e.g., silver or Coomassi staining), and sequence analysis (for nucleic acids and peptides).

[0082] As used herein, the term “hyaluronic acid” (HA) refers to glycosaminoglycans (e.g., linear glycosaminoglycan polymers formed from repeating units of the disaccharide [-D-glucuronic acid-b1,3-N-acetyl-D-glucosamine-b1,4-]n), also known as hyaluronan, which are composed of naturally occurring disaccharide repeats of N-acetylglucosamine and glucuronic acid, as well as derivatives of hyaluronic acid having chemical modifications such as esters, amide derivatives, alkylamine derivatives, low-molecular-weight and high-molecular-weight forms of hyaluronic acid, and crosslinked forms such as hyaluronic acid. Thus, the disaccharide chain may be linear or non-linear. Hyaluronic acid can be crosslinked by binding with crosslinking agents such as thiols, methacrylates, hexadecylamides, and tyramines. Hyaluronic acid can also be directly crosslinked with formaldehyde and divinyl sulfone.Examples of hyaluronan include hyaluronan A, hyaluronan B, and hyaluronan G-F20 (Hargittai M and I Hargittai, "More Conversations with Hyaluronan Scientists," from Hyaluronan - From Basic Science to Clinical Applications, Balazs EA, Ed., Vol. 3, 2011, PubMatrix, Edgewater, NJ; Cowman MK et al., Carbohydrate Polymers 2000, 41:229-235; Takigami S et al., Carbohydrate Polymers, 1993, 22:153-160; Balazs EA et al., "Hyaluronan, its cross-linked derivative-Hylan-and their medical applications," in Cellulosics Utilization: Research and Rewards in Cellulosics, Proceedings of Nisshinbo International Conference on Cellulosics Utilization in the Near Future (Eds Inagaki, H and Phillips) GO), Elsevier Applied Science (1989), NY, pp. 233-241; Koehler L et al., Scientific Reports, 2017, 7, article no. 1210; and Pavan M et al., Carbohydr Polym, 2013, 97(2): 321-326. These include, but are not limited to, the entirety of which is incorporated herein by reference.

[0083] The term "hyaluronic acid" or HA includes HA itself and its pharmaceutically acceptable salts, such as sodium hyaluronate. HA can be formulated into pharmaceutically acceptable salt forms. Pharmacopoeia of HA can be prepared using conventional techniques.

[0084] The term "high molecular weight" or "HMW" in the context of the hyaluronic acid of this invention means at least 2.5m as determined by the method of European Pharmacopoeia 9.0 ("Sodium Hyaluronate"), page 3584 (the entirety of which is incorporated herein by reference). 3 / kg (i.e., 2.5m 3 This refers to hyaluronic acid with an intrinsic viscosity of (1 / kg or more). In short, intrinsic viscosity [η] is given by the Martin formula: Log 10 (n r -1 / c) = log 10 It is calculated by linear least squares regression analysis using [η] + κ[η]c. In some embodiments, the high molecular weight hyaluronic acid is at least 2.9m 3 / kg (i.e., 2.9m 3 It has an intrinsic viscosity of 1 / kg or more.

[0085] As used herein, the term “ocular disorder” is intended to broadly encompass any abnormality of the eye (e.g., disease, illness, injury) that may benefit from the co-administration of a bioactive agent (therapeutically or prophylactically). The disorder may be at any stage and may be acute or chronic. For example, HMWHA and the bioactive agent may be co-administered at the initial, intermediate, or progressive stage of an ocular disorder. The disorder may be of any severity (e.g., mild, moderate, or severe). In some embodiments, the ocular disorder may be an anterior segment, posterior segment, or both. The ophthalmic compositions and methods described above are useful for treating, preventing, or delaying the onset or recurrence of ocular hypertension and glaucoma.

[0086] As used herein, the term “ocular surface” refers to the cornea and conjunctiva, as well as a portion thereof including the conjunctiva covering the upper and lower eyelids. HA and prostaglandin analogs may be co-administered topically to one or more portions of the ocular surface (e.g., including the entire ocular surface).

[0087] "Pharmacologically acceptable salts" include both acid-added and base-added salts. Any one of the pharmaceutically acceptable salts of HA or other compounds described herein (e.g., prostaglandin analogs and other intraocular pressure-lowering agents) is intended to encompass any and all pharmaceutically acceptable salt forms. Preferred pharmaceutically acceptable salts described herein are pharmaceutically acceptable acid-added salts and pharmaceutically acceptable base-added salts.

[0088] "Pharmacologically acceptable acid addition salts" refer to salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, which retain the biological efficacy and properties of the free base and are not biologically or otherwise undesirable. They also include salts formed with organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonic acids. Salts of amino acids such as alginates, glucons, and galacturonic acids are also considered (see, for example, Berge SM et al., [Non-Patent Literature 29], the entire work of which is incorporated herein by reference). Acid addition salts of basic compounds may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt, according to methods and techniques familiar to those skilled in the art.

[0089] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological efficacy and properties of a free acid and is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. Pharmaceutically acceptable base addition salts may be formed using metals or amines such as alkalis and alkaline earth metals or organic amines. Examples of salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins (see the above literature by Berge et al.). In some embodiments, the pharmaceutically acceptable salt is a sodium salt (see "Sodium Hyaluronate" on page 3583 of European Pharmacopoeia 9.0, as incorporated herein by reference).

[0090] As used herein, the terms “subject,” “patient,” and “individual” refer to human or non-human animals. Subject also refers to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a bird or fish. Therefore, the method may be carried out in medical and veterinary settings. Non-human animal subjects may be, for example, pets or animal models with or without eye diseases. In some embodiments, the subject is an adult. In other embodiments, the subject is a child under 18 years of age (e.g., infant, adolescent, or boy).

[0091] The term “topical administration” is used herein in its conventional sense, meaning local delivery to a desired anatomical site, such as the ocular surface. The fluid containing high molecular weight hyaluronic acid may be applied directly or indirectly to the ocular surface by any means that allows an effective amount of the fluid to come into contact with the ocular surface. For example, the fluid may be applied directly to the ocular surface via eye drops or washes, or indirectly via a delivery agent (i.e., a fluid delivery agent) that comes into contact with the ocular surface or other parts of the eye. An example of a delivery agent is a particle (e.g., a microparticle or nanoparticle) that is coated with the fluid and / or releases the fluid onto the ocular surface. Such particles may be composed of a variety of materials, such as natural or synthetic polymers. In some embodiments, the delivery agent may be administered itself as a dropper.

[0092] The terms “treat,” “treating,” and “treatment” include alleviating, improving, slowing, reversing, or inhibiting the progression of a medical abnormality such as ocular hypertension or glaucoma, or one or more symptoms or complications associated with such abnormality, and alleviating, improving, or eradicating one or more causes of such abnormality.

[0093] The present invention is described only illustratively by the embodiments in the specification and drawings, and is not limited thereto, and includes all variations, modifications, substitutions, and combinations that experts may take from the complete documentation of this application, taking into account and / or in combination with their specific knowledge.

[0094] All patents, patent applications, provisional applications, and publications mentioned or cited herein are incorporated herein by reference in their entirety, including their drawings and tables, unless they conflict with the express teachings herein.

[0095] The following are examples illustrating the procedure for carrying out the present invention. These examples should not be construed as limiting. Unless otherwise noted, all percentages are given by weight, and all solvent mixing ratios are given by volume.

[0096] ( Example - Comparison of the combination of latanoprost and high molecular weight hyaluronic acid with latanoprost alone in reducing intraocular pressure. ) Materials and methods A sterile bulk solution for manufacturing COMFORT SHIELD® MDS eye drops (i.com medical GmbH, Munich, Germany) was used as a vehicle for preparing a prototype latanoprost bulk solution (PLBS). The vehicle consisted of 0.15% w / v hiran A (2.9m) dissolved in phosphate-buffered saline (8.035 g / l NaCl; 1.2 mmol / l Na2HPO4 / NaH2PO4; pH 7.4). 3 It contained HA with an intrinsic viscosity of 1 / kg. Latanoprost was obtained from Yonsung Fine Chemicals Co. Ltd. (Gyeonggi-do, South Korea). PLBS was prepared by medi-pharm Laboratorium GmbH (Falkensee, Germany) by dissolving 20±1 μg / ml of latanoprost in a vehicle.

[0097] Sterile 10 ml bottles equipped with an ophthalmic squeeze dispenser (OSD) were obtained from Aptar Radolfzell GmbH (Radolfzell, Germany). Medi-pharm Laboratorium GmbH prepared two batches of prototype latanoprost test samples (PLTS-A) for stability screening by aseptically filling the Aptar bottles with 9 ml of PLBS and closing them with the OSD. Sterile Novelia® 11 ml soft bottles with a 1.6 mm valve diameter and PureFlow® 1500 droppers were obtained from Nemera (La Verpillier, France). Pharmpur GmbH (Königsbrunn, Germany) prepared prototype latanoprost test samples (PLTS-N) for IOP self-testing by aseptically filling the Novelia bottles with 10 ml of PLBS and closing them with the dropper. Because latanoprost tends to adsorb to the silicone part of the infusion tube, these test samples had to be kept vertical to minimize contact between the solution and the infusion tube. The latanoprost concentration in the PLTS-N bottle used for self-testing was 19 μg / ml.

[0098] Xalatan® eye drops (PFIZER OFG Germany GmbH, Berlin, Germany), containing 50 μg / ml latanoprost, 0.2 mg / ml benzalkonium chloride, and 6.3 mg / ml phosphate, were used as a comparative sample in the IOP self-test.

[0099] Comfort Shield® MDS 0.15% Hyran A eye drops (i.com medical GmbH, Munich, Germany), consisting of a prototype latanoprost test sample vehicle, was used as a control during the washout period of the IOP self-test.

[0100] subject The subject (TS) was a 71-year-old male with a healthy ocular surface, no history of eye trauma or surgery, no history of stored eye drop use, and untreated ocular hypertension unrelated to glaucoma.

[0101] method In preliminary tests, 25 μg / ml and 50 μg / ml of latanoprost were added to the vehicle, and the solution was stirred at 40°C for 18 hours. The latanoprost content was determined by HPLC using a 5 μm, 150.0 × 4.0 mm Hypersil BDS C18 column (VDS optilab) and a UV detector (200 nm). Regardless of the starting dose, 20.8 μg / ml of latanoprost was found to dissolve in the vehicle, compared to the solubility of 12.9 μg / ml of latanoprost in water (PubChem Compound Summary for CID 5311221, Latanoprost. National Center for Biotechnology Information).

[0102] Samples from two batches of PLTS-A were stored for 6 months at room temperature (15–25°C), 2–8°C, 25°C / 60% relative humidity (RH), and 40°C / 75% RH. Initially, at 4 weeks, 3 months, and 6 months, the samples were visually inspected for appearance (clarity) and presence of particles, and tested for pH, latanoprost content, and weight loss.

[0103] Through self-testing, IOP was measured using the hand-held icare HOME Model rebound tonometer TA022 (Icare Finland Oy, Vantaa, Finland) (Liu, J. et al., Icare Home Tonometer: A Review of Characteristics and Clinical Utility, Clin Ophthalmol, 2020. 14: p. 4031-4045). Three measurements were taken, and the average value was recorded.

[0104] IOP is known to fluctuate significantly over a 24-hour (circadian) period, and furthermore, the time of peak IOP is known to differ among patients (Barkana, Y. et al., "Clinical utility of intraocular pressure monitoring outside of normal office hours in patients with glaucoma," Arch Ophthalmol, 2006. 124(6): p. 793-7; Mansouri, K. et al., "Review of the measurement and management of 24-hour intraocular pressure in patients with glaucoma," Surv Ophthalmol, 2020. 65(2): p. 171-186). Little is known about the daily (interday) variability of IOP. Therefore, TS measured IOP in both eyes for seven consecutive days at 08:00 (8am), 11:00 (11am), 15:00 (3pm), 19:00 (7pm), and 22:00 (10pm). The individual peak IOP times (11:00) of the TS were selected for IOP monitoring through a screening test.

[0105] Eight weeks prior to the self-test, TS administered one drop of Comfort Shield eye drops (=vehicle) to each eye in the morning and evening. The self-test lasted five weeks, with IOP measured daily at 11:00 for both eyes. During weeks 1, 3, and 4, the vehicle was applied in the morning and evening. During weeks 2 and 5, the vehicle was applied only in the morning (7:00-8:00), and one drop of latanoprost eye drops was administered to each eye between 19:00 and 20:00. During week 2, Xalatan eye drops (50 μg / ml latanoprost) were applied, and during week 5, PLTS-N eye drops (19 μg / ml latanoprost) were administered.

[0106] result Stability screening The results of stability screening for two batches of prototype latanoprost test samples (PLTS-A) are summarized in Tables 2 and 3.

[0107] Table 2: Stability test results for PLTS-A, batch E030219 [Table 2]

[0108] Table 3: Stability test results for PLTS-A, batch E040219 [Table 3] *nd=not determined

[0109] To study individual circadian rhythms and diurnal variations, TS measured IOP for seven consecutive days. TS's IOP peaked late in the morning and then continuously decreased until evening (see Table 4).

[0110] Table 4 Circadian and intraday variations of IOP in the right eye (OD) and left eye (OS) of TS [Table 4]

[0111] Therefore, IOP measurements were performed at 11:00 AM to compare the effectiveness of latanoprost eye drops in the eyes of TS patients. Furthermore, since significant differences were observed daily, IOP measurements were performed for seven consecutive days, both with and without latanoprost eye drops.

[0112] The results of the self-test are summarized in Table 5.

[0113] Table 5. IOP values ​​before (week 1) and during (week 2) application of commercially available latanoprost eye drops 50 μg / mL, and before (week 4) and during (week 5) application of PLTS-N 19 μg / mL latanoprost eye drops. [Table 5]

[0114] When commercially available eye drops containing 50 μg / ml of latanoprost were applied, intraocular pressure (IOP) decreased by 3.24 mmHg, from an average baseline value of 27.62 mmHg to an average value of 24.38 mmHg. On the other hand, when the prototype latanoprost test sample PLTS-N, containing only 19 μg / ml of latanoprost, was applied, IOP decreased by 5.87 mmHg, from an average baseline value of 27.30 mmHg to an average value of 21.43 mmHg.

[0115] conclusion In the eyes of subjects (TS), commercially available eye drops containing 50 μg / ml of latanoprost reduced IOP by an average of 3.24 mmHg. In contrast, the prototype eye drops PL20 containing 19 μg / ml of latanoprost reduced IOP by an average of 5.87 mmHg. These findings suggest that the combination of latanoprost and high molecular weight hyaluronic acid is more effective in reducing IOP than latanoprost alone.

[0116] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in light thereof are proposed to those skilled in the art and should be understood to be included in the spirit and scope of this application and the appended claims. Furthermore, any element or limitation of any invention or embodiment disclosed herein may be combined with any and / or all other elements or limitations (individually or in any combination) of any other invention or embodiment disclosed herein, and all such combinations are intended within the scope of the invention and are not limited thereto.

Claims

1. Hyaluronic acid and, It comprises at least one active ingredient containing a prostaglandin analog, The aforementioned HA acts as a transport vehicle for the prostaglandin analog to the eye. The aforementioned HA is at least 2.9 m ３ It has an intrinsic viscosity of / kg, The aforementioned prostaglandin analogs are a) Latanoprost at concentrations of 2 micrograms per milliliter to 45 micrograms per milliliter; b) Bimatoprost at a concentration of less than 100 micrograms per milliliter; c) Travoprost at a concentration of less than 30 micrograms per milliliter; d) Tafluprost at a concentration of less than 15 micrograms per milliliter; or e) Unoprostone at a concentration of less than 1500 micrograms per milliliter including Ophthalmic composition.

2. An ophthalmic composition according to claim 1, The ophthalmic composition contains no substances other than the at least one active ingredient that do not naturally exist in the human eye. Ophthalmic composition.

3. An ophthalmic composition according to claim 1, The aforementioned ophthalmic composition does not contain preservatives (it is preservative-free). Ophthalmic composition.

4. An ophthalmic composition according to claim 1, The prostaglandin analog is present at concentrations lower than those effective in treating, preventing, and / or delaying the onset or recurrence of ocular hypertension or glaucoma without the HA. Ophthalmic composition.

5. An ophthalmic composition according to claim 1, The prostaglandin analog comprises latanoprost, and the latanoprost is present at a concentration of less than 30 micrograms per milliliter. Ophthalmic composition.

6. An ophthalmic composition according to claim 1, The prostaglandin analog comprises latanoprost, which is present in concentrations ranging from 10 micrograms to 40 micrograms per milliliter, 15 micrograms to 25 micrograms per milliliter, or 20 micrograms to 25 micrograms per milliliter. Ophthalmic composition.

7. An ophthalmic composition according to claim 1, The prostaglandin analog comprises latanoprost, which is present at a concentration of 20 micrograms per milliliter. Ophthalmic composition.

8. An ophthalmic composition according to claim 1, The prostaglandin analog comprises latanoprost, which is present at a concentration ranging from 20 micrograms per milliliter to 25 micrograms per milliliter. Ophthalmic composition.

9. An ophthalmic composition according to claim 1, The prostaglandin analog comprises bimatoprost, which is present at a concentration of less than 100 micrograms per milliliter. Ophthalmic composition.

10. An ophthalmic composition according to claim 1, The prostaglandin analog comprises travoprost, which is present at a concentration of less than 30 micrograms per milliliter. Ophthalmic composition.

11. An ophthalmic composition according to claim 1, The prostaglandin analog comprises tafluprost, which is present at a concentration of less than 15 micrograms per milliliter. Ophthalmic composition.

12. An ophthalmic composition according to claim 1, The prostaglandin analog contains unoprostone, which is present at a concentration of less than 1500 micrograms per milliliter. Ophthalmic composition.

13. An ophthalmic composition according to any one of claims 1 to 4, The ophthalmic composition is an aqueous solution that is stable for at least 4 weeks, at least 3 months, or at least 6 months under one or more of the following conditions: (i) a temperature of 15 to 25°C, (ii) a temperature of 2 to 8°C, or (iii) a temperature of 25°C at a relative humidity of 60%. Ophthalmic composition.

14. An ophthalmic composition according to any one of claims 1 to 4, The hyaluronic acid has a molecular weight of at least 3 million dollars tons. Ophthalmic composition.

15. An ophthalmic composition according to any one of claims 1 to 4, The hyaluronic acid has a molecular weight in the range of 3 million to 4 million dollars tons. Ophthalmic composition.

16. An ophthalmic composition according to any one of claims 1 to 4, The aforementioned ophthalmic composition is a) pH 5.8-8.5; b) Osmotic pressure 240-330 mosmol / kg; c) NaCl concentration of 7.6–10.5 g / l; and / or d) Phosphate concentration of 1.0–1.4 mmol / l Having one, two, three, or all four of them Ophthalmic composition.

17. An ophthalmic composition according to any one of claims 1 to 4, The ophthalmic composition is a colorless, transparent solution that does not contain any visible impurities. Ophthalmic composition.

18. An ophthalmic composition according to any one of claims 1 to 4, The ophthalmic composition is sterile. Ophthalmic composition.

19. An ophthalmic composition according to any one of claims 1 to 4, The aforementioned hyaluronic acid exists in the form of COMFORT SHIELD (registered trademark) preservative-free sodium hyaluronate eye drops. Ophthalmic composition.

20. An ophthalmic composition according to any one of claims 1 to 4, The at least one active ingredient includes an additional agent that lowers intraocular pressure. Ophthalmic composition.

21. An ophthalmic composition according to claim 20, The aforementioned additional drug lowers intraocular pressure by a mechanism of action different from that of the at least one prostaglandin analog. Ophthalmic composition.

22. The ophthalmic composition according to claim 21, The aforementioned additional drugs are beta-adrenergic blockers, cholinergic agonists, carbonic anhydrase inhibitors, or adrenergic receptor blockers. Ophthalmic composition.

23. The ophthalmic composition according to claim 22, The aforementioned additional drugs include timolol. Ophthalmic composition.

24. An ophthalmic composition according to any one of claims 1 to 4, The ophthalmic composition is formulated as eye drops, eye wash, or contact lenses. Ophthalmic composition.

25. An ophthalmic composition according to any one of claims 1 to 4 for lowering intraocular pressure in the eye of a subject, or for maintaining lowered intraocular pressure.

26. An ophthalmic composition according to any one of claims 1 to 4 for treating, preventing, and / or delaying the onset or recurrence of ocular hypertension or glaucoma in a human subject.

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