WO2023078557A1

WO2023078557A1 - Method and system for the treatment of vitreous floaters

Info

Publication number: WO2023078557A1
Application number: PCT/EP2021/080678
Authority: WO
Inventors: Hakan KAYMAK
Original assignee: Kaymak Hakan
Priority date: 2021-11-04
Filing date: 2021-11-04
Publication date: 2023-05-11

Abstract

The present invention provides methods and systems for the treatment of patients suffering from a condition characterized by the presence of vitreous floaters in the patients' eye and includes a ready-to-use topical ophthalmic formulation, comprising a buffered aqueous solution and a long-lasting mydriatic for use in a method of treatment to ameliorate a subject's visual impairment caused by opacities and/or floaters of the vitreous in the subject's eye.

Description

Method and system for the treatment of vitreous floaters

TECHNICAL FIELD

The present invention concerns the field of ophthalmology and provides methods and systems for the treatment of subjects suffering from a condition characterized by the presence of vitreous floaters in the subjects’ eye.

BACKGROUND

The term “floater” or “vitreous floater” describes mobile structures or deposits in the vitreous body (“vitreous”) of a subject’s eye that are so dense that they can impair the visual impression. The clinical presentation of a subject with floaters includes visual symptoms often described as gray, linear, hair-like structures with round points that appear more prominent against bright backgrounds (a white wall, clear sky, or white lit computer screen) but also translucent strings, or a “spider web-like” image. The perception of the “floating” of these elements occurs in head or eye movements, sometimes with a prominent overdamping effect. Floaters are also called “mouches volantes” (for “flying flies” in French). As reported by Huang et al. (“Vitreous Floaters and Vision: Current Concepts and Management Paradigms” doi: 10.1007/978-1-4939- 1086-1_45. In: Vitreous: in Health and Disease, Springer Science+Business Media, New York 2014) studies which employed utility value analysis determine that floaters had a significantly negative impact upon quality of life and symptoms could be much more disturbing than previously appreciated; the degree to which floaters lower the visual quality of life turned out to be equivalent to age-related macular degeneration (AMD) and greater than diabetic retinopathy and glaucoma, as well as mild angina pectoris, mild stroke, or colon cancer; the perceived negative impact of floaters had long been underscored as subjects would be willing to take on average an 11% risk of death and a 7% risk of total blindness and to trade 1.1 years out of every 10 years remaining in their lives to eradicate floaters.

The vitreous body is a complex structure which consists of 99% water and hyaluronic acid and is organized by a framework of very thin collagen fibers. During the aging process, the proportion of hyaluronic acid decreases with the result that water molecules are released and collagen fibers aggregate. With increasing thickness of the collagen fibers and depending on their position in relation to the visual axis or proximity to the retina, agglomerates of these fibers are perceived as floating opacities. In a later phase, the vitreous humor detaches itself from the retina, as a result, a so-called "white ring" forms in some people, a particularly thick strand of collagen that is often located directly in front of the central retina. Most people hardly notice floaters, but others are considerably disturbed by their floaters. Two treatment options for floaters have become established. The surgical pars plana vitrectomy (PPV) and vitreolysis with a short-pulsed Nd:YAG laser. While the evidence and the safety profile for short-pulsed Nd: YAG laser treatment have not yet been conclusively clarified, surgical vitrectomy is a long-established procedure. A PPV effectively removes floaters and the surgical risks have decreased with the introduction of minimally invasive surgical techniques, yet induced cataract, iatrogenic retinal foramina, retinal detachment and endophthalmitis belong to the spectrum of serious complications. Ophthalmologists thus are often reluctant to recommend such surgery when weighing up the risk of complications, for the fact that the clinical picture of the floater problem can often not be objectified and the subject's vision, provided there are no ophthalmological co-morbidities, is often good.

The iris of the eye contains the pupil with two groups of smooth muscles; a circular group: M. sphincter pupillae, and a radial group: M. dilator pupillae. When the sphincter contract, the iris decreases or constricts the size of the pupil. The dilator, innervated by sympathetic nerves from the superior cervical ganglion, cause the pupil to dilate when they contract. The pupil gets wider in the dark and narrower in light. When narrow, the diameter is 2 to 4 millimeters. In the dark it will be the same at first, but will approach the maximum distance for a wide pupil 3 to 8 mm. At the peak age of 15, the dark- adapted pupil can vary from 4 mm to 9 mm with different individuals. After 25 years of age, the average pupil size decreases. There is evidence that just by way of mydriasis, i.e. the widening of the pupil, the visual impairment of a subject suffering from one or more vitreous floaters can be considerably reduced. This is due to a mere optical effect, as a narrow bundle of light entering the eye through a smaller pupil produces a sharper and more contrasted “image” of the vitreous’ inhomogeneity or fibrous agglomerate projected on the retina than a broader bundle of light entering through a larger pupil with more light passing by the floaters and falling onto the retina unobstructed, thus generating a much less contrasted “image” of the floater or no perceivable floater “image” at all.

Yet, this floater treatment option which, as such, does not bear any risk of considerable complications for it is based on a mere non-invasive pharmacological intervention reportedly falls short in its practical application with the subject for the following reasons: Mydriatics which, by way of pharmacological interaction on the pupil’s smooth muscle groups, widen the pupil and thus reduce a subject’s perception of vitreous floaters. For example, tropicamide is an antimuscarinic drug that produces short acting mydriasis and cycloplegia. It is normally used to support ophthalmological examination of the lens, vitreous humor, and retina (dilated fundus examination). 1% tropicamide is also administered in combination with p-hydroxyamphetamine, a sympathomimetic causing a stimulation of the iris dilator muscle increasing dilation; a sympathomimetic most commonly used along with tropicamide, is 2.5% phenylephrine hydrochloride.

However, most such mydriatics applied in practice to date only act in a short term fashion for only a few hours along the day and all are formulated to produce a so-called “full mydriasis” with maximum widening of the pupil and with no considerable pupillary light reflex left to compensate for sudden occurrences of bright light and glare. It is observed that, with a larger pupil, there is a significant increase in optical aberrations in the eye and thus in a functional decrement in visual performance and in one or more unwanted effects such as reduced contrast sensitivity, blurred vision, increased glare and increased photophobia (sensitivity to light). There is also caused a concomitant cycloplegia, i.e. a paralysis of the eye’s ciliary muscle, leaving the eye unable to accommodate refraction to near objects, which corresponds to a lack of near vision or temporary functional hyperopia (far sightedness) characterized by reduced or blurred vision at near distances. To reduce or lower the risk of the aforementioned side-effects associated with mydriasis it may be desirable to use lower concentrations of a pharmaceutical agent. However, lower concentrations may not provide sufficient control efficacy. Additionally, use of pharmaceutical agents that require long term topical or systemic applications at more frequent intervals, e.g. many times a day, may likely be associated with non- compliance and non-adherence to such medication regimens leading to reduced therapeutic efficacy.

It therefore is an object present invention to provide methods and means for a tolerable and well acceptable pharmacological therapy for subjects suffering from a condition characterized by the presence of vitreous floaters in the subjects’ eye, i.e. to ameliorate the visual impairment of a subject conferred by the one or more vitreous floater (“floater treatment”) specifically by means of altering the subject’s pupil size through mydriasis. The therapy should be easily performed, ideally by employing a one-time dose per treatment day only; the therapy should be well apt for long-term or chronical treatment over a long period of time; and the therapy should thereby avoid any unwanted or not tolerable side effect for the subject, including loss of near vision, increased glare and increased photophobia.

SUMMARY OF THE INVENTION

The present invention solves the underlying technical problem by providing a method of treatment and means for the method of treatment, said method and means are mainly characterized in an individual, in particular in a personalized, dosing plan and treatment regime for the treatment of vitreous floaters in a subject.

The present invention solves the underlying technical problem in a first aspect by providing a ready-to-use topical ophthalmic formulation comprising a specific long lasting mydriatic for use in a method of treatment of a condition of visual impairment caused by opacities and/or floaters of the vitreous (“vitreous floaters”) in a subject’s eye (“floater treatment”), to be applied in an individual dosing regimen. More particular, the specific dosing regimen in connection with the specific ophthalmic formulation brings about a long lasting and sub mydriatic effect resulting in a substantive decrease in the subject’s perception of his/her vitreous floaters, yet avoiding the impairments normally expected from mydriasis by pharmacological intervention such as overly increased sensitivity to glare, photophobia and a substantial loss of clear near vision due to a substantial non tolerable accommodative lag or asthenopia.

In the context of the invention, there is also provided, in a second aspect, a method to determine the individual adequate dose of the long lasting mydriatic which is apt for a chronic treatment of said vitreous floaters in a subject. By providing specific upper and lower limits in the amplitude of a subject’s drug induced increase in pupil diameter (IPD) after administration of the specific ophthalmic formulation of the present invention or his/her pupillary light reflex (“PLR”) after its administration and by providing the proper setting to assess the subject’s individual IPD and/or PLR, the method provides for a maximum floater suppressing effect for the subject while conserving the subject’s individual pupillary response to glare.

Without wishing to be bound by the theory, the invention makes use of the surprising finding that a specific long-lasting mydriatic in an ophthalmic formulation at a specifically low concentration in combination with a specific pre-determined individual dosing regimen which is established on the basis of specific parameters of each subject’s individual pupillary dynamic response, significant beneficial effects can be provided to the floater treatment described herein, while at the same time adverse effects known from floater treatments known to date can be avoided, this is much to the benefit of the subject as it increases a subject’s compliance to adhere to the therapy over a long period of time, which, as an additional beneficial effect, can thus also relieve or ameliorate additional somatic disorders that may have established after a long suffering from floaters.

According to the invention, the specific long-lasting mydriatic is selected from atropine or its derivatives and is present in the ophthalmic formulation at very low doses of preferably from about 0.001 wt% (%by weight) to about 0.025 wt%, or more preferred from about 0.001 wt% to about 0.01 wt%. Such low doses of a compound are more common to homeopathic medicine and correspond to potencies of D4 and D5, respectively, in homeopathic terms. This specifically brings about a particular pharmaco-dynamic and pharmaco-kinetic action and time course in a human subject’s eye which cannot be achieved by other known mydriatic compounds and formulations. The specific pharmaco-dynamic and pharmaco-kinetic action and time course of the atropine based ophthalmic formulation of the present invention in a human subject’s eye surprisingly combines very well with the individual dosing regimen established according to the present invention to bring about the beneficial technical effects as described herein.

Accordingly, in one particular aspect, there is provided a method of treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous (“vitreous floaters”) in a subject’s eye in need thereof. According to this aspect of the invention, the method of treatment comprises the step of topically administering an ophthalmic formulation comprising a long-lasting mydriatic to said eye in an amount such that the induced increase in pupil diameter (IPD) of said eye at photopic illuminance levels is not less than 1.0 mm and not more than 2.5 mm above the eye’s pupil diameter as before the administration of the ophthalmic formulation.

In more particular embodiments thereof, the decisive IPD, after administration of the ophthalmic formulation, ranges from 1.0 to 2.0 mm or from 1.0 to 1.5 mm or from 1.2 to 2.5 mm or from 1.2 to 2.0 mm or from 1.2 to 1.8 mm or from 1.2 to 1.5 mm or from 1.5 to 2,5 mm or from 1.5 to 2.2 mm or from 1.5 to 2.0 mm or from 1.5 to 1.8 mm or from 1.8 to 2.5 mm or from 1.8 to 2.2 mm or from 1.8 to 2.0 mm or from 2.0 to 2.5 mm. In one preferred variant, IPD is from 1.2 to 1.8 mm.

In a closely related aspect, there is provided a method of treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous (“vitreous floaters”) in a subject’s eye in need thereof. According to the invention, the method of treatment comprises, in the alternative to the previous aspect or in addition thereto, the step of topically administering an ophthalmic formulation comprising a long- lasting mydriatic to said eye in an amount such that the absolute pupil constriction amplitude of said eye’s PLR to changes in illumination from mesopic illuminance levels to photopic illuminance levels is not less than 1.5 mm and not more than 4 mm.

In a particular embodiment thereof , for subjects having an age of less than 45 years at the time of said treatment the ophthalmic formulation comprising the long-lasting mydriatic is topically administered to said eye in an amount such that the absolute pupil constriction amplitude of the PLR is from 2.0 mm to 4.0 mm; and for subjects having an age of 45 years or more at the time of said treatment the ophthalmic formulation comprising the long-lasting mydriatic is topically administered to said eye in an amount such that the absolute pupil constriction amplitude of the PLR is from 1.5 mm to 3.0 mm.

In more particular embodiments, the decisive PLR amplitude generally may range from 1.5 to 3.5 mm or from 1.5 to 3.0 mm or from 1 .5 to 2.5 mm or from 1 .5 to 2.0 mm or from 2.0 to 4.0 mm or from 2.0 to 3.5 mm or from 2.0 to 3.0 mm or from 2.0 to 2.5 mm or from 2.5 to 4.0 mm or from 2.5 to 3.5 mm or from 2.5 to 3.0 mm or from 3.0 to 4.0 mm or from 3.0 to 3.5 mm or from 3.5 to 4.0 mm. In one preferred variant, PLR amplitude is from 1 .5 to 2.5 mm. More particular, for subjects having an age of 45 years or more at the time of said treatment, it is contemplated that the decisive PLR amplitude may range from 1.5 to 2.5 mm or from 1.5 to 2.0 mm or from 2.0 to 3.0 mm or from 2.0 to 2.5 mm or from 2.5 to 3.0 mm, and for subjects having an age of less than 45 years at the time of said treatment, it is contemplated that PLR amplitude may range from 2.0 to 3.5 mm or from 2.0 to 3.0 mm or from 2.0 to 2.5 mm or from 2.5 to 4.0 mm or from 2.5 to 3.5 mm or from 2.5 to 3.0 mm or from 3.0 to 4.0 mm or from 3.0 to 3.5 mm or from 3.5 to 4.0 mm.

In a closely related aspect, there is provided a method of treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous (“vitreous floaters”) in a subject’s eye in need thereof. According to the invention, the method of treatment comprises, in the alternative to the previous aspect or in addition thereto, a step wherein the ophthalmic formulation comprising the long-lasting mydriatic is topically administered to said eye in an amount such that the average pupil constriction amplitude of said eye’s PLR to changes in illumination from a mesopic illuminance level to a photopic illuminance level after the administration of said ophthalmic formulation is reduced to at least 60% but to not less than 30%, preferably to not less than 40% of the average pupil constriction amplitude of said PLR as before the administration of said ophthalmic formulation.

It is contemplated that in connection with the methods of the invention described herein, the mesopic illuminance level corresponds to from about 1 to about 3 cd/m² and the photopic illuminance level corresponds to from about 100 to about 250 cd/m².

In more specific variants of the methods of the invention, PLR is induced by immediate changes in full-field illumination by white light from a mesopic illuminance level to a photopic illuminance level within less than 100 msec, more preferably within less than 30 msec.

In more specific variants of the methods of the invention, IPD and/or PLR is assessed not before 40 min, preferably not before 1 hour and up to 4 hours after the topical administration of said amount the ophthalmic formulation to said eye. In a preferred variant, the IPD and/or PLR is assessed between 1 hour and 2 hours after the topical administration.

In a related aspect, the invention further provides a method for determining a subject’s individual dosing regimen for the topical ophthalmic formulation, comprising a long- lasting mydriatic, particularly selected from atropine and a pharmaceutically acceptable salt, derivative or prodrug thereof, for use in a treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous in the subject’s eye.

In one embodiment, the method comprises at least the step of: topically administering an ophthalmic formulation comprising a long-lasting mydriatic to said eye in an amount such that the increase in pupil diameter (IPD) of said eye at photopic illuminance levels is not less than 1.0 mm and not more than 2.5 mm above the eye’s pupil diameter as before the administration of said ophthalmic formulation. In more particular embodiments thereof, the decisive IPD after administration of the ophthalmic formulation ranges from 1.0 to 2.0 mm or from 1.0 to 1.5 mm or from 1.2 to 2.5 mm or from 1.2 to 2.0 mm or from 1.2 to 1.8 mm or from 1.2 to 1.5 mm or from 1.5 to 2,5 mm or from 1.5 to 2.2 mm or from 1.5 to 2.0 mm or from 1.5 to 1.8 mm or from 1.8 to 2.5 mm or from 1.8 to 2.2 mm or from 1.8 to 2.0 mm or from 2.0 to 2.5 mm. In one preferred variant, IPD is from 1.2 to 1.8 mm.

In another embodiment, the method, alternatively or additionally, comprises the step of: topically administering the ophthalmic formulation to said eye in an amount such that the absolute pupil constriction amplitude of said eye’s PLR to changes from a mesopic illuminance levels to photopic illuminance levels (“PLR amplitude”) is not less than 1.5 mm and not more than 4 mm. In yet more particular embodiments, the PLR amplitude is from 1.5 to 3.5 mm or from 1.5 to 3.0 mm or from 1.5 to 2.5 mm or from 1.5 to 2.0 mm or from 2.0 to 4.0 mm or from 2.0 to 3.5 mm or from 2.0 to 3.0 mm or from 2.0 to 2.5 mm or from 2.5 to 4.0 mm or from 2.5 to 3.5 mm or from 2.5 to 3.0 mm or from 3.0 to 4.0 mm or from 3.0 to 3.5 mm or from 3.5 to 4.0 mm. In one preferred variant, PLR amplitude is from 1.5 to 2.5 mm.

In another embodiment, the method, alternatively or additionally, comprises the step of: topically administering the ophthalmic formulation to said eye in an amount such that the average pupil constriction amplitude of said eye’s PLR to changes from a mesopic illuminance levels to photopic illuminance levels after the administration of said ophthalmic formulation is reduced to at least 60% and to no less than 30% of the average pupil constriction amplitude of said PLR before the administration of said ophthalmic formulation (“PLR reduction”). In yet more particular embodiments, alone or in combination with a PLR amplitude range defined herein, the PLR reduction is from 60 to 35% or from 60 to 40% or from 60 to 45% or from 60 to 50% or from 60 to 55% or from 55 to 30% or from 55 to 35% or from 55 to 40% or from 55 to 45% or from 50 to 30% or from 50 to 35% or from 50 to 40% or from 50 to 45% or from 45 to 30% or from 40 to 35% or from 45 to 30% or from 45 to 35% or from 45 to 40% or from 40 to 30% or from 40 to 35% or from 35 to 30%. In one preferred variant, PLR reduction is from 60 to 40%.

In preferred embodiments thereof, the method further comprises at least the steps of: initially assessing the average pupil constriction amplitude of said eye’s PLR to changes from a mesopic illuminance level to a photopic illuminance levels before administration of the ophthalmic formulation and storing the subject’s average pupil constriction amplitude as the reference level (100%); and topically administering an initial predetermined dose of the ophthalmic formulation to said eye; and, consecutively, assessing the average pupil constriction amplitude of said eye’s PLR to changes from a mesopic illuminance level to a photopic illuminance level after administration of said initial dose and storing the subject’s average pupil constriction amplitude as the induced level; and calculating the subject’s individual reduction of average pupil constriction amplitude as a fraction of said induced level by said initial dose and said reference level.

In preferred embodiments thereof, the method further comprises at least the steps of: entering the individual level of reduction of the average pupil constriction amplitude of PLR and said initial dose amount into a lookup-table and retrieving from the look-up table a result, selected from an indication of an individual treatment dosage regimen and an indication to increase or decrease or maintain said initial dose; and outputting or displaying said result to the user. In a preferred embodiment, the look-up table comprises the decisive parameters as listed in Table 1. In other words, if the average pupil constriction amplitude of a subject’s PLR, is reduced by an initial dose of 1 drop (25 pL) of 0.001 wt% to 90% of original PLR, the subject’s individual dose will be set to 1 drop (25 pL) of 0.005 wt%; if the average pupil constriction amplitude of a subject’s PLR, is reduced by an initial dose of 1 drop (25 pL) of 0.001 wt% to 80% or 70% of original PLR, the subject’s individual dose will be set to 2 drops (50 pL) of 0.001 wt%; if the average pupil constriction amplitude of a subject’s PLR, is reduced by an initial dose of 1 drop (25 pL) of 0.001 wt% to 60% 30% of original PLR, the subject’s individual dose will be maintained at 1 drop (25 pL) of 0.001 wt%. If the average pupil constriction amplitude of a subject’s PLR, is reduced by an initial dose of 2 drops (50 pL) of 0.001 wt% to 90% of original PLR, the subject’s individual dose will be set to 1 drop (75 pL) of 0.005 wt%; if the average pupil constriction amplitude of a subject’s PLR, is reduced by an initial dose of 2 drops (50 pL) of 0.001 wt% to 80% or 70% of original PLR, the subject’s individual dose will be set to 3 drops (75 pL) of 0.001 wt%; if the average pupil constriction amplitude of a subject’s PLR, is reduced by an initial dose of 2 drops (50 pL) of 0.001 wt% to 60% 40% of original PLR, the subject’s individual dose will be maintained at 2 drops (50 pL) of 0.001 wt%; and if the average pupil constriction amplitude of a subject’s PLR, is reduced by an initial dose of 2 drops (50 pL) of 0.001 wt% to 30% to 20% of original PLR, the subject’s individual dose will be set to 1 drops (25 pL) of 0.001 wt%; and so on. A skilled person will contemplate the process to read the subject’s individual dose from this look-up table.

Note that the look-up table of table 1 has been established on the basis of an average drop volume of 25 pL per dose. For other drop volumes as the may be dispensed from other containers or eye drop dispensers which may well vary from, for example, 15 pL to 60 pL, which corresponds to a 5-fold variation in the dose dispensed and eventually instilled to the subject, the values given in the look-up table of table 1 must be adapted accordingly or the drop volumes must be adapted to 25 pL per dose, for example by selecting the appropriate dispenser or container.

In the context of the present invention, the terms “treatment” or “treating” are used herein to denote delaying the onset of, preventing, inhibiting, alleviating the effects of, or regressing a disease or a symptom thereof in a subject. In the context of the present invention, the term “subject” is used to describe a human or non-human individual, to whom treatment according to the methods of the present disclosure is provided.

Human applications are anticipated by the present disclosure. Both pediatric and adult subjects are included. In any of the methods described herein, the subject can be at least 18 months old, e.g., 18 months or older, 2 years or older, 4 years or older, 6 years or older, 10 years or older, 13 years or older, 14 years or older, 16 years or older, 18 years or older, 21 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older. In any of the methods described herein, the subject can at the same time be 25 years or younger, 30 years or younger, 35 years or younger, 40 years or younger, 45 years or younger, 50 years or younger, 60 years or younger, 65 years or younger, 70 years or younger, 75 years or younger, 80 years or younger, 85 years or younger, 90 years or younger.

In a related aspect, there is also provided a specific treatment plan which in connection with the individual pre-determined dose of the long-lasting mydriatic brings about a maximum floater suppressing effect for the subject while conserving the subject’s individual pupillary response to glare over the whole day and avoiding other adverse side effects. In a particular embodiment thereof, said determined amount of the ophthalmic formulation is administered to said eye at the beginning of daytime. Preferably, said determined amount of the ophthalmic formulation is administered to said eye each treatment day in a one-time dose. In a preferred variant, said determined amount of the ophthalmic formulation is administered in the morning after bedtime. In yet a preferred variant, said determined amount of the ophthalmic formulation is administered in the morning after sunrise. In yet a preferred variant, said determined amount of the ophthalmic formulation is administered in the morning when illumination reaches a photopic level.

According to the invention, there is also provided a ready-to-use topical ophthalmic formulation, comprising a buffered aqueous solution and from about 0.001 wt% (by weight) to about 0.025 wt% of a long-lasting mydriatic, where the long-lasting mydriatic is selected from atropine and a pharmaceutically acceptable salt thereof. In a preferred embodiment, the long lasting mydriatic is present at a concentration of from 0.005 wt% to 0.01 wt% In a more preferred embodiment, the long lasting mydriatic is present at a concentration of about 0.005 wt%. In another more preferred embodiment, the long lasting mydriatic is present at a concentration of about 0.01 wt%. Atropine for the preparation of the formulations contemplated may be in the form any suitable pharmaceutically acceptable salt thereof, including mineral salts and organic salts; atropine may also be employed in a suitable prodrug form.

Tropane alkaloids are toxic secondary metabolites produced by Solanaceae plants.

Among them, plants from Atropa belladonna produce significant amounts of hyoscyamine, which undergoes racemization to atropine (L-hyoscyamine) during isolation. As tropane alkaloids, scopolamine and hyoscyamine, are common in the family Solanaceae, they are also present in plants of the genera Brugmansia, Datura, and Hyoscyamus, including, but not limited to henbane (Hyoscyamus niger), mandrake (Mandragora officinarum), angel's trumpets (Brugmansia spp.), jimsonweed (Datura stramonium), tomato (Solanum lycopersicum), the sorcerers' tree (Latua pubi flora), and deadly nightshade (Atropa belladonna). Atropine is the major alkaloid in Atropa belladonna roots. It can be extracted from the plant as free bases using basic aqueous solutions or as salts using acidified solutions. The obtained native liquid extracts are purified using repeatedly performed solvent extraction operations. Typically, the alkaloids are extracted from basic solutions with an appropriate organic solvent. Best results were obtained when chloroform was used. This solvent is widely used for purification of tropane alkaloids. The resulting organic solutions are stripped by acidic solutions and the alkaloids are recovered in the stripping solutions as salts. In a particular embodiment thereof, the ophthalmic formulation comprises atropine. Liquid membrane or pertraction processes are an attractive alternative of extraction.

In a particular embodiment, the ophthalmic formulation thus comprises Atropine in the form of a plant extract from a plant of the family Solanaceae, more preferred from Datura spp. or from Atropa belladonna, preferably a root extract. The plant extract is standardized to atropine content, but may contain other active compounds, including other tropane alkaloids and/or derivatives, thus supporting the therapeutic effect of the atropine compound in the context of the present invention.

In a particular embodiment, the ophthalmic formulation further comprises one or more cardenolide glycoside compound, which is selected from Digitalis purpurea leaf extract and Digitalis lanata leaf extract. In a variant thereof, ophthalmic formulation further comprises the cardenolide glycoside compound Aesculus hippocastanum extract. Without wishing to be bound to theory, the cardenolide glycoside compound acts to support accommodative efforts in particular in presbyopic subjects and prevent potential visual fatigue due too accommodative dysfunction, by balancing the parasympatholytic action of the long lasting mydriatic on the eye’s ciliary muscle. The term “accommodative dysfunction” refers to a reduction or a decrease or an imbalance or instability of the accommodative function or amplitude, or an imbalance between accommodation and eyes’ convergence that may result in one or more symptoms of vision disturbance and/or difficulties in viewing at near and intermediate distances.

It is contemplated that the ophthalmic formulation, in particular function enhanced embodiments, comprises at least one further compound selected from the group of active ophthalmic compounds, consisting of: pilocarpine, phentolamine, oxymetazoline, brimonidine, epinephrine, ephedrine, naphazoline, dipivefrin, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, a cholinesterase inhibitor, such as neostigmine, echothiophate, diisopropyl fluorophosphates, or physostigmine, and any pharmaceutically acceptable salt, ester, prodrug or other active derivative thereof. These compositions may act alone or synergistically, for example, to improve the accommodative and focusing ability of the eye while minimizing the side effects from each other compound. It is also contemplated that the one or more additional effect brought about by the enhanced embodiment is selected from the group of ocular conditions to be treated or therapeutic effects, consisting of: progressive myopia, pathologic myopia, amblyopia, cycloplegia, mydriasis, allergic conjunctivitis, conjunctival hyperemia, red eye, glaucoma, ocular hypertension, night vision symptoms post refractive surgery, presbyopia, accommodative esotropia, glaucoma, ocular hypertension, accommodative insufficiency, hyperopia, anisocoria, amblyopia, tonic pupil, parasympathetic denervation, complications arising after refractive surgery, corneal scars, and iatrogenic conditions after cataract surgery.

In a preferred embodiment, the ophthalmic formulation comprises a low concentration pH-buffering system, in particular a citric acid-based pH-buffering system at a concentration of from 2 mmol/L to 6 mmol/L of citric acid and in particular the ophthalmic formulation has a pH of less than 4.90 or less than pH 4.85. It has been surprisingly found that this pH-buffering system prevents the unwanted hydrolytic degradation of atropine to tropic acid in aqueous solution which is notably accelerated in low-dose atropine formulations with reduced concentrations of atropine. At the same time, the low concentration buffer allows for a highly tolerable application to the subject with no itching and burning sensation during and after topical application of the eye drops, despite the acidic pH of the formulation. The low concentration pH-buffering system according to the invention thus provides a ready-to use liquid storage-stable low-dose ophthalmic atropine composition. In particular embodiments, the pH-buffering system is present in the ophthalmic formulation at a concentration of from 2 to 6 mmol/L citric acid, or from 2 to 5 mmol/L citric acid, or from 2 to 4 mmol/L citric acid, or from 2 to 3 mmol/L citric acid, or from 3 to 6 mmol/L citric acid, or from 3 to 5 mmol/L citric acid, or from 3 to 4 mmol/L citric acid, or from 4 to 5 mmol/L citric acid, or from 4 to 6 mmol/L citric acid, or from 5 to 6 mmol/L citric acid. In more preferred variant, the concentration is from 2.5 to 3.5 mmol/L citric acid.

It is thus contemplated that the ophthalmic formulation does not comprise any other pH-buffering system, such as an additional monobasic, bi- or multibasic salt and its corresponding acids, other than the citrate buffer system. In a preferred embodiment, the ophthalmic formulation is free, in particular substantially free of any of ethanoic acid/sodium ethanoate buffers, boric acid/sodium borate, monobasic sodium phosphate/dibasic sodium phosphate, monobasic sodium phosphate/sodium citrate, as well as of any suitable amphoteric buffer systems including HEPES, MOPS, PIPES, and MES.

In a preferred embodiment, the ophthalmic formulation further comprises an antioxidative component, selected from ascorbic acid, preferably in the form of Vitamin C (L-ascorbic acid or L-ascorbate), or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the antioxidative component is present in a amount of from 1 to 200 pmol/L, preferably from 10 to 150 pmol/L. In a preferred variant, the antioxidative component confers to the ophthalmic formulation a total antioxidant capacity, FRAP value, of greater than 100 pmol/L, preferably greater than 150 pmol/L. Without wishing to be bound to theory, the antioxidative component acts as a protective agent against oxidative stress to the eye’s tissue and in particular to the structure of the eye’s natural lens and the eye’s cornea. Ascorbic acid is present in the lens and surrounding ocular humors at a concentration 50-fold higher than in plasma. It can act a protect the lens from UV induced oxidative damage and to regenerate vitamin E and glutathione to further increase antioxidant capacity. The antioxidative component prevents the other active compounds of the ophthalmic formulation from being degraded by oxidative processes during storage. The antioxidative component also brings about this protective effect during and after application of the formulation to the eye, in particular in combination with the low concentration of the buffer in the buffered aqueous solution of the ophthalmic formulation. More particular, the vitreous body consumes oxygen and it has been suggested that the main function of ascorbic acid in the vitreous is to detoxify ROS by acting as an antioxidant on its own. Ascorbic acid may function in the vitreous to decrease molecular oxygen concentrations. The action of ascorbic acid in the eye and in particular in the vitreous is a question of concentrations, where at lower concentrations ascorbic acid may predominate as antioxidant, while at higher concentrations, as achieved by pharmacological overdosing, ascorbic acid may lead to the formation of H2O2.

In a preferred embodiment, the ophthalmic formulation is free, in particular substantially free, of any chelating agent or of any additional chelating agent other than the citric acid buffering system and ascorbic acid. In a preferred embodiment, the ophthalmic formulation is free, in particular substantially free, of any metal ion chelator, particularly selected from bicarboxylic acids, tricarboxylic acids, and amino polycarboxylic acids, including monomeric polyacids: EDTA, cyclohexanediamine tetraacetic acid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTPA), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccmic acid (DMSA), aminotrimethylene phosphonic acid (ATPA), and each of their salts thereof; and pyrophosphates, tripolyphosphates, and, hexametaphosphates; and chelating antibiotics including chloroquine and tetracycline; and nitrogen-containing chelating agents containing two or more chelating nitrogen atoms including diimines and 2,2'- bipyridines; and polyamines including cyclam (1,4,7,11-tetraazacyclotetradecane), hexadecyclam, tetramethylhexadecylcyclam; and diethylenetriamine (DETA), spermine, diethylnorspermine (DENSPM), diethylhomo-spermine (DEHOP), and desferroixamines (DFO).

In a preferred embodiment, the ophthalmic formulation is free, in particular substantially free of any preservative and detergent. In the context of the present invention, compositions are considered “substantially free” if not more than 0.01 wt%, and more typically not more than 0.005 wt% of a substance or compound is present. More preferred, the ophthalmic formulation is free, in particular substantially free of any one of benzalkonium chloride, cetrimide or cetrimonium salts, benzododecinium salts, cetylpyridinium chloride, polidronium chloride, polyquaternium-1, polyquaternium-42, sepazonium chloride, phenylmercury salts, mercuriothiolate, mercurobutol, chlorhexidine, polyhexamethylene biguanide, chlorobutanol, phenylethanol, benzyl alcohol, phenol, m-cresol, phenoxyethanol, parahydroxybenzoic acid, methylparaben, and propylparaben, and of any pharmaceutically acceptable salt, derivative or prodrug thereof.

In another preferred embodiment, the ophthalmic formulation is free, in particular substantially free, of any macromolecular viscosity modifier. More preferred, the ophthalmic formulation is free, in particular substantially free of any one of polysaccharidic polymers and cellulosic polymers, including hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. In preferred variant thereof, the formulation has a dynamic viscosity of from 1.5 to 5 cP (mPa s). In another preferred variant thereof, the formulation has a dynamic viscosity of 1 cP (mPa s).

In alternative preferred embodiment, the ophthalmic formulation comprises at least one macromolecular viscosity modifier to adjust the viscosity of the formulation to a dynamic viscosity of from 10 to 40 cP (mPa s). A preferred viscosity modifier is selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and derivatives therefrom.

In a preferred embodiment, the ophthalmic formulation is formulated as a ready-to-use topical ophthalmic formulation, particularly in a ready-to-use concentration. It is contemplated to provide the ophthalmic formulation in an easy to use packaging or container for use by the subject and in a preferred embodiment according to the individual dosing scheme and treatment plan in accordance with the treatment method of the present invention. That is, in a preferred embodiment the topical ophthalmic formulation is present in the container in a ready-to-use concentration. The container is a multi-dose container. In an alternative embodiment, the container is a single-use or single-dose container. In is contemplated that the ophthalmic formulation is, preferably filtered through a sterile particle filter, filled in to a polymer container, such as polyethylene, polypropylene or low-density polyethylene containers. The containers may be pre-formed containers, alternatively the containers are formed and filled in a blow-fill-seal process. In a particular embodiment, the volume of a multi-dose container is from 5 mL to 10 mL. In a particular embodiment, the drop volume of a single-use container is 0.6 mL to 0.2 mL.

In a preferred embodiment, the topical ophthalmic formulation is prepared to be applicable as a single “one-drop-only” or “two-drops” dosage to achieve the correct individual dosing scheme of the subject. This is preferably accomplished by the provision which contain the ophthalmic formulation in various ready-to-use concentrations as described herein and which can be selected for the individual treatment. In an additional or alternative specific variant thereof, there are provided various containers to select from, which vary in the volume of the drop dispensed, a higher drop volume resulting in a higher individual dose at the same drug concentration. The drop volume is preferably predetermined through the individual design of each container or, in the alternative, and individual volume to be dispensed by the container can be selected by the user or pre-selected by, for example, the pharmacist in accordance with the subject’s individual dosing scheme, i.e. the prescription. It is contemplated that the individual average drop volume of a container may range from 15 pL to 60 pL. In a particular embodiment, the drop volume of a multidose container is 35 pL ± 5 pL. In a particular embodiment, the drop volume of a single-use container is 20 pL ± 5 pL.

In an alternative embodiment, the container is a single dose container, containing the individual one-time daily dose for a subject in accordance with the subject’s individual dosing scheme. In preferred embodiments, the volume of the ophthalmic formulation contained in the single-use container is from 20 pL to 50 pL, assuming a 5 to 10 pL residual remaining in the single-use container after dispensing the one-time dose.

According to one aspect of the invention, there is provided the ophthalmic formulation as described herein for use in the method of treatment as described herein. More particular, according to the present invention there is provided a ready-to-use topical ophthalmic formulation, comprising buffered aqueous solution and from about 0.001 wt% to about 0.025 wt% of a long-lasting mydriatic, selected from atropine and a pharmaceutically acceptable salt thereof, for use in a method of treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous in the subject’s eye, the method of treatment comprising the step of topically administering the ophthalmic formulation to said eye in an amount such that the absolute pupil constriction amplitude of said eye’s PLR to changes from a mesopic illuminance levels to photopic illuminance levels is not less than 1.5 mm and not more than 4 mm.

More particular, according to the present invention there is provided a ready-to-use topical ophthalmic formulation, comprising buffered aqueous solution and from about 0.001 wt% to about 0.025 wt% of a long-lasting mydriatic, selected from atropine and a pharmaceutically acceptable salt thereof, for use in a method of treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous in the subject’s eye, the method of treatment comprising: topically administering the ophthalmic formulation to said eye in an amount such that the average pupil constriction amplitude of said eye’s PLR to changes from a mesopic illuminance levels to photopic illuminance levels after the administration of said ophthalmic formulation is reduced to at least 60% and to no less than 30% of the average pupil constriction amplitude of said PLR before the administration of said ophthalmic formulation.

According to another aspect of the invention, there is provided a kit of parts for use in a method of treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous in the subject’s eye. According to the invention, the kit comprises: an eye drop container or dispenser, containing the ophthalmic formulation which comprises the long-lasting mydriatic as described herein; and instructions for use to establish the subject’s individual treatment dose, comprising the steps of the method of treatment as characterized herein.

In another embodiment the kit further comprises: a medical device for establishing a subject’s individual PLR, the device being specifically designed in carrying out the steps of the method as characterized herein.

In connection with the present invention there is provided a device for assessing the intensity of the visually perceived vitreous floaters. The device being characterized in a uniformly lit screen or Ulbricht sphere in front of the subject’s eye, which is illuminated in bright light, preferably white light, at photopic light levels. Without wishing to be bound by the theory, A subject’s vitreous floaters are best visible to the subject when looking at a bright and uniformly lit unpatterned target, just as the covered sky or a white wall. The device further includes a system specifically designed to produce one or more dark spots, or patterns simulating the appearance of a vitreous floater, of varying size and contrast displayed within the field of view provided by the uniformly lit screen. In a preferred embodiment, the uniformly lit screen and the system to produce the dark spots, or patterns simulating the appearance of a vitreous floater, are in the form of a video display, such as a computer monitor display, or in the form of a video projection system to project onto the screen in front of the subject’s eye, a particular variant, to project onto the curved screen of the calotte of an Ulbricht sphere. The device further includes a controller running a software with an algorithm. In a preferred embodiment, the algorithm, preferably in connection with an input device operable by the subject, allows for a semi-automated assessment of the subjective visual perception of the subject’s vitreous floater, wherein one or more dark spots, or patterns simulating the appearance of a vitreous floater, of varying size and contrast are displayed within the central field of view of the subject as provided by the uniformly lit screen in front of the subject’s eye.

The algorithm, preferably by way of a Bayesian iterative psychophysical test approach known as such (e.g. FrACT®), allows for the one or more dark spots or patterns simulating the appearance of a vitreous floater are displayed to match in size and contrast to the vitreous floaters subjectively perceived by the subject at the time of the test. In a particular embodiment, there is a pre-test session where the subject is asked to select the “type” of his/her individual floater appearance in categories, preferable selected from: “cloudy”, “spider web like”, ’’dark spot(s)”, “loop- or rope-like”. For the actual test, the simulated pattern for the psychophysical comparison between the simulated pattern and the actually perceived vitreous floater is selected according to the category selected in the pre-test session.

In the following, more particular embodiments are disclosed:

Embodiment 1: A ready-to-use topical ophthalmic formulation, comprising a buffered aqueous solution and from about 0.001 wt% to about 0.025 wt% of a long- lasting mydriatic, selected from atropine and a pharmaceutically acceptable salt, derivative or prodrug thereof, for use in a method of treatment of a condition of visual impairment caused by opacities and/or floaters of the vitreous in subject’s eye suffering from this condition, the method of treatment comprising: topically administering the ophthalmic formulation to said eye in an amount such that the absolute pupil constriction amplitude of said eye’s pupillary light reflex (PLR) to changes from a mesopic illuminance levels to photopic illuminance levels is not less than 1.5 mm and not more than 4 mm.

Embodiment 2: The ophthalmic formulation of embodiment 1 , wherein said the absolute pupil constriction amplitude of said eye’s pupillary light reflex is from 2.0 mm to 4.0 mm for subjects having an age of less than 45 years and from 1.5 mm to 3.0 mm for subjects having an age of 45 years or more at the time of said treatment. Embodiment 3: A ready-to-use topical ophthalmic formulation, comprising a buffered aqueous solution and from about 0.001 wt% to about 0.025 wt% of a long- lasting mydriatic, selected from atropine and a pharmaceutically acceptable salt, derivative or prodrug thereof, for use in a method of treatment of a condition of visual impairment caused by opacities and/or floaters of the vitreous in subject’s eye suffering from this condition, the method of treatment comprising the step of topically administering an ophthalmic formulation comprising a long-lasting mydriatic to said eye in an amount such that the drug induced increase in pupil diameter (IPD) of said eye at photopic illuminance levels is not less than 1.0 mm and not more than 2.5 mm above the eye’s pupil diameter as before the administration of said ophthalmic formulation.

Embodiment 4: A ready-to-use topical ophthalmic formulation, comprising a buffered aqueous solution and from about 0.001 wt% to about 0.025 wt% of a long- lasting mydriatic, selected from atropine and a pharmaceutically acceptable salt, derivative or prodrug thereof, for use in a method of treatment of a condition of visual impairment caused by opacities and/or floaters of the vitreous in subject’s eye suffering from this condition, the method of treatment comprising: topically administering the ophthalmic formulation to said eye in an amount such that the average pupil constriction amplitude of said eye’s pupillary light reflex to changes from a mesopic illuminance levels to photopic illuminance levels after the administration of said ophthalmic formulation is reduced to at least 60% and to no less than 30% of the average pupil constriction amplitude of said pupillary light reflex before the administration of said ophthalmic formulation.

Embodiment 5: The ophthalmic formulation of any one of the embodiments 1 to

4, wherein said eye’s pupillary diameter (IPD) and/or pupillary light reflex (PLR) as after administration of the ophthalmic formulation are each assessed from 1 hour to 4 hours after the topical administration of said amount the ophthalmic formulation to said eye.

Embodiment 6: The ophthalmic formulation of any one of the embodiments 1 to

5, wherein the mesopic illuminance level is about 1 to 3 cd/m² and the photopic illuminance level is about 100 to 250 cd/m².

Embodiment 7: The ophthalmic formulation of any one of the embodiments 1 to

6, the method being further characterized in that said amount the ophthalmic formulation is administered to said eye each treatment day in a one-time dose at the beginning of daytime only.

Embodiment 8: The ophthalmic formulation of any one of the embodiments 1 to

7, comprising the long lasting mydriatic at a concentration of from 0.005 to 0.01% (w/w).

Embodiment 9: The ophthalmic formulation of any one of the embodiments 1 to

8, further comprising ascorbic acid and/or a pharmaceutically acceptable salt thereof.

Embodiment 10: The ophthalmic formulation of any one of the embodiments 1 to

9, further comprising one or more cardenolide glycoside compounds, selected from Digitalis purpurea leaf extract and Digitalis lanata leaf extract.

Embodiment 11 : The ophthalmic formulation of any one of the embodiments 1 to

10, having a citric acid-based pH-buffering system at a concentration of from 2 mmol/L to 6 mmol/L citric acid and the ophthalmic formulation having a pH of less than 4.90 or less than pH 4.85.

Embodiment 12: The ophthalmic formulation of any one of the embodiments 1 to

11, which is free of any preservative and detergent.

Embodiment 13: The ophthalmic formulation of any one of the embodiments 1 to

12, which is free of any macromolecular viscosity modifier.

Embodiment 14: A kit for use in a treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous in the subject’s eye, comprising: an eye drop container or dispenser, containing an ophthalmic formulation which comprises from about 0.001 to about 0.025% (w/w) atropine or a pharmaceutically acceptable salt thereof or as characterized in any one of the embodiments 8 to 13; and instructions for use to establish the subject’s individual treatment dose, comprising the steps of the method of treatment as characterized in any one of the embodiments 1 to 7.

Embodiment 15: The kit of embodiment 14, further comprising: a medical device for establishing a subject’s individual pupil light reflex, the device being specifically designed in carrying out the steps of the method as characterized in any one of embodiments 1 to 7.

Embodiment 16: A method of determining a subject’s individual dose of a topical ophthalmic formulation, comprising a buffered aqueous solution and from about 0.001 wt% to about 0.025 wt% of a long-lasting mydriatic, selected from atropine and a pharmaceutically acceptable salt thereof, for use in a treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous in the subject’s eye, the method comprising the steps of: topically administering the ophthalmic formulation to said eye in an amount such that the average pupil constriction amplitude of said eye’s pupillary light reflex to changes from a mesopic illuminance levels to photopic illuminance levels after the administration of said ophthalmic formulation is reduced to at least 60% and to no less than 30% of the average pupil constriction amplitude of said pupillary light reflex before the administration of said ophthalmic formulation.

Embodiment 17: The method of embodiment 16, comprising the steps of: initially assessing the average pupil constriction amplitude of said eye’s pupillary light reflex to changes from a mesopic illuminance level to a photopic illuminance levels before administration of the ophthalmic formulation and storing the subject’s average pupil constriction amplitude as the reference level (100%); topically administering an initial predetermined dose of the ophthalmic formulation to said eye; consecutively, assessing the average pupil constriction amplitude of said eye’s pupillary light reflex to changes from a mesopic illuminance level to a photopic illuminance level after administration of said initial dose and storing the subject’s average pupil constriction amplitude as the induced level; and calculating the subject’s individual reduction of average pupil constriction amplitude as a fraction of said induced level by said initial dose and said reference level.

Embodiment 18: The method of embodiment 17, further comprising the steps of: entering the individual level of reduction of the average pupil constriction amplitude and said initial dose amount into a lookup-table and retrieving from the look-up table a result, selected from an indication of an individual treatment dosage regimen and an indication to increase or decrease or maintain said initial dose; and outputting or displaying said result to the user. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows in an overlay graph the course of the average pupil diameter of n=9 subjects before (0 h) and after (1 h, 4 h, 8 h) binocular instillation of the mydriatic atropine.

Figure 2 shows a typical pupillary light reflex (PLR) of an individual subject upon an instant change in illumination from scotopic (3 cdr ²) to photopic illumination (85 cd rm²).

Figure 3 schematically depicts the arrangement of one embodiment of a biomedical device (310) specifically designed to be used in the method of the present invention.

Figures 4A and 4B shows graphs of the average (n=8) accommodative response of subjects before (0 h) and after (0,5 h, 1,0 h, 4,0 h, 8,0 h) binocular instillation of the mydriatic atropine.

Figure 5 is in an overlay graph of the average (n=9) subjective impact of the currently perceived vitreous floater(s) on a subject’s vision (“floater intensity”) as assessed in a subjective scale.

Figure 6 shows the average (n=12) perceived vitreous floater(s) (“floater intensity”) as assessed by volunteers suffering from viterous floaters in a subjective scale: I.

Figure 7 shows the susceptibility to glare light (135 lx) as assessed by the level of decrease in contrast sensitivity (logCS) at two spatial frequencies (3 and 6 cycles per degree) (n=14).

EXAMPLES

The following examples illustrate some of the experiments leading to the formulations and methods according to the invention, however, should not be construed to limit the scope of the claims in any way.

Example 1 : Pupillary Light Reflex (PLR)

From young volunteers (n=12; 40% male; age: 28,1 ± 3,0 years) written informed consent was obtained after explanation of the nature and possible consequences of this study. The tenets of the Declaration of Helsinki were followed. All subjects had clear optical media and no ocular pathology. Pupillary light reflex was assessed by use of the Aladdin® (Topcon, Inc.) device. Figure 1 shows in an overlay graph the course of the average pupil diameter of n=8 subjects before (0 h) and after (1 h, 4 h, 8 h) binocular instillation of the mydriatic atropine at a standard dose of 1 drop of 20 pL volume of 0.005% atropine sulfate per each eye. The graph marks the average pupil size at scotopic (3 cdm^-2) and at phototopic (85 cdm^-2) illumination as assessed through dynamic pupillometry with the Aladdin® (Topcon, Inc.). In the lower part, the respective amplitudes of the pupil dynamic are shown. Figure 2 shows a typical pupillary light reflex (PLR) of an individual subject upon an instant change in illumination from scotopic (3 cdm^-2) to photopic illumination (85 cdm^-2) and back before (220) and 4 hours after (210) binocular instillation of atropine as described in Figure 1.

Example 2: Device for Assessment of Pupillary Light Reflex (PLR) and Vitreous Floaters

Figure 3 schematically depicts the arrangement of one embodiment of a biomedical device (310) specifically designed to be used in the method of the present invention for assessing the dynamic pupil response of a subject and/or objectively assess the subject’s perception of his/her vitreous floaters, before and after instillation of a mydriatic. The device (310) specifically includes a screen (320) facing towards the subject. The screen (320) is designed to be homogeneously illuminated at various intensities bring about scotopic and photopic illumination to elicit the pupillary light reflex (PLR) of the subject upon sudden changes from scotopic to photopic illumination and back. In one particular embodiment, the screen (320) is also designed to be homogeneously illuminated at various intensities such to make visible to the subject his/her the visual impairments (e.g. greyish clouds, black ropes or dots) conferred by the vitreous floaters. In another embodiment, one or more darker areas can be presented within the screen (320), that can be matched in size and contrast to the subject’s actually perceived vitreous floaters by means of operative interaction with the subject to objectively assess the intensity of the subject’s current floater perception. The device (310) further includes a pupillometry device (330) to remotely assess the subject’s pupil diameter, preferably in the form of an infrared video retinoscopy comprising an edge detecting algorithm for the iris and pupil margin. The device (310) preferably further includes a, preferably user operable or automatically movable, mount (340) to bring or hold the device (310) in a matching measuring position in front of the subject’s eye. The device is preferably connected to a separate control device (350) via wired or wireless data connection (355). The control device (350) comprises a computing device (351) and a data display (352).

Example 3: Individual Dosing Regime on the Basis of PLR

The device according to Example 2 provides a software to assess a subject’s individual subjective impact of the currently perceived vitreous floater(s) on the subject’s vision (i.e. “floater intensity”) in a subjective scale: level 1 = “no disturbance”, level 2 = “tolerable disturbance”, level 3 = “badly tolerable disturbance”, level 4 = “not tolerable disturbance”, and level 5 “very bad”.

The device provides a software to assess a subject’s individual dosing scheme for the treatment of vitreous floater(s), to reduce subject’s perceived floater intensity, on the basis of the objectively assessed drug induced reduction in subject’s elicited PLR according to the invention. The software includes a look-up table to generate the individual dose from a pre-determined initial dose.

Table 1:

Example 4: Accommodative Lag

From volunteers (n=18; 40% male) written informed consent was obtained after explanation of the nature and possible consequences of this study. The tenets of the Declaration of Helsinki were followed. All subjects had clear optical media and no ocular pathology. Accommodative response amplitude (near response) was assessed by use of the WAM5500 (Grand Seiko, Inc. Japan) device. Accommodation was stimulated with printed text presented at various distances. In static mode, three measurements were taken for various stimulus distances and averaged. Each subject’s individual near point was individually assessed taking into account the subject’s objective refraction and correction. Figures 4A and 4B shows graphs of the average accommodative response of subjects before (0 h) and after (0,5 h, 1,0 h, 4,0 h, 8,0 h) binocular instillation of the mydriatic atropine each at an individual dose of atropine sulfate per each eye to bring about a relative PLR amplitude in a subject which is reduced to either 60% or only 20% of the original relative PLR (PLR=100%) of that subject before the instillation of atropine. Figure 4A shows the results for younger subjects at ages 25 to 40 yr (n= 12) ; Figure 4B shows the results for older subjects at ages 45 to 55 yr (n=6).

In yet another test with the subjects at ages 25 to 40 yrs (n= 12) , it was found that, after instillation of a dose of the ophthalmic formulation of the invention, which brings about a reduction in PLR to about 50% of original PLR, although there was a slight and significant increase in near accommodation distance by (Mean±Std.Dev.) 7.4 ± 3.4 cm (p<0,01) at about 1.5 hours after drug instillation, the average high contrast distance- corrected near visual acuity (DCNVA) at 40 cm did not change significantly from -0.06 ± 0.07 logMAR before to +0.01 ± 0.03 logMAR after drug instillation.

Example 5: Floater Intensity after Drug Instillation

From volunteers (n=9; 30% male) written informed consent was obtained after explanation of the nature and possible consequences of this study. The tenets of the Declaration of Helsinki were followed. All subjects had clear optical media and no ocular pathology, but suffered from vitreous floaters. The atropine ophthalmic formulation according to the present invention was instilled to the subjects at an individual dose of the long lasting mydriatic leading to a reduction in subject’s relative PLR to either 70%, to 50%, or to only 20% of the subject’s original PLR level (PLR=100% before the instillation of the mydriatic), PLR, floater intensity and pupil diameter were assessed with the devices and methods illustrated in Examples 1, 2, and 3 before and after 0.5, 1.0, 1.5, 4.0, and 8.0 hours after initial atropine instillation (non-linear scale). Figure 5 is in an overlay graph of the average (n=9) subjective impact of the currently perceived vitreous floater(s) on a subject’s vision (“floater intensity”) as assessed in a subjective scale: level 1 = “no disturbance”, level 2 = “tolerable disturbance”, level 3 = “badly tolerable disturbance”, level 4 = “not tolerable disturbance”, and level 5 “very bad”, at three different levels of reduction in PLR. On a second scale there is shown the course of the average pupil diameter of these subjects at the three different levels of reduction in the subject’s relative PLR. In a second experiment, the mydriatic was instilled at doses to individually reduce PLR to either 90%, 70%, 60%, 50%, 40%, 30% 20%, or only 5% of the subject’s original PLR level. Subjects were measured more than once starting immediately after instillation of the mydriatic to achieve the various PLR reductions. Each individual PLR reduction was rounded to the nearest 10% and sorted into the nearest category of either 90%, 70%, 60%, 50%, 40%, 30%, 20%. The 5% category was selected for subjects showing only a slight PLR or no PLR at all.

Figure 6 shows the average (n=9) perceived vitreous floater(s) (floater intensity) as assessed by volunteers suffering from vitreous floaters in a subjective scale: level 1 = “no disturbance”, level 2 = “tolerable disturbance”, level 3 = “badly tolerable disturbance”, level 4 = “not tolerable disturbance”, and level 5 “very bad”, each at different levels of individual PLR reduction as assessed after 1-2 hours after initial atropine instillation (using the devices and methods illustrated in Figures 1, 2, and 3; 100% PLR corresponds to subject’s original unimpaired level of PLR, 5% PLR corresponds to the most reduced PLR after instillation of a considerable dose of the mydriatic atropine). According to one embodiment of the present invention, the instillation of an individual dose of atropine to bring about a reduction in a subject’s PLR to about at least 60% and to not less than 30%, preferably to not less than 40% of the average pupil constriction amplitude already leads to relevant reduction in the subject’s perception of his/her/floater(s) and considerable amelioration of the visual impairment.

Example 6: Sensitivity to Glare

From volunteers (n=9; 40% male) written informed consent was obtained after explanation of the nature and possible consequences of this study. The tenets of the Declaration of Helsinki were followed. All subjects had clear optical media and no ocular pathology, but suffered from vitreous floaters. The atropine ophthalmic formulation according to the present invention was instilled to the subjects at an individual dose of the long lasting mydriatic leading to a reduction in subject’s relative PLR to either 90%, 60%, 50%, 30% or 20%. Subjects were measured more than once starting immediately after instillation of the mydriatic to achieve the various PLR reductions. Each individual PLR reduction was rounded to the nearest 10% and sorted into the nearest category of either 90%, 70%, 60%, 50% or 30% The 20 % category was selected for subjects showing 20% PLR or less, including only a slight PLR or no PLR at all.

Figure 7 shows the susceptibility to glare light (135 lx) as assessed by the level of decrease in contrast sensitivity (logCS) at two spatial frequencies (3 and 6 cycles per degree) as assessed according to the F.A.C.T. protocol (n=14) by the visual function analyzer OPTEC® 6500P (Stereo Optical Co., Inc., Chicago, USA) under photopic conditions (85 cdm^-2) at each at different levels of individual PLR reduction as assessed after 1-2 hours after initial atropine instillation (using the devices and methods illustrated in Figures 1, 2, and 3; 100% PLR corresponds to subjects original unimpaired level of PLR, 5% PLR corresponds to the most reduced PLR after instillation of a considerable dose of the mydriatic atropine). According to one embodiment of the present invention, the instillation of an individual dose of atropine to bring about a reduction in a subject’s PLR to about at least 60% and to not less than 30%, preferably to not less than 40% of the average pupil constriction amplitude does not impair the subject’s susceptibility to glare light (135 lx) to a considerable amount.

In yet another test on contrast sensitivity by means of the semi-automated Bayesian Freiburg Visual Acuity and Contrast Test (FrACT®, Bach, M. “The Freiburg Visual Acuity Test-variability unchanged by post-hoc re-analysis.” Graefes Arch Clin Exp Ophthalmol 2007(245): 965-971. doi: 10.1007/s00417-006-0474-4) with sinusoidal gratings at 3, 6, and 12 cpd and with glare effected by a bright white LED (10.000 med, 20° beam angle) fixed at the frame of the FraACT®-stimulus screen, and with the screen being placed in front of the subject at a distance of 3 m, the volunteers performed as listed in Table 2. There was no significant reduction in contrast sensitivity (logCS).

Table 2:

Example 7: Atropine Ophthalmic Formulations

For the herein described examples 1 to 6 ophthalmic formulations of various atropine concentrations, 0.001wt%, 0.005wt%, 0.01wt%, and 0.05wt% (as calculated based on atropine sulfate monohydrate) were prepared from stock solutions of standardized atropine drug preparations to final compositions as listed in Table 3. In addition, further ophthalmic formulations with enhanced functionality have been prepared as listed in Table 4.

Table 3: Standard Atropine Ophthalmic Formulation

Table 4: Enhanced Atropine Ophthalmic Formulation

Drug stability:

Atropine ophthalmic formulations as prepared (Tables 3 and 4) were filled into Blow- Fill-Seal EDO-containers in an amount of approx.0.4 mL each, sealed, in batches of 5, in metallized polymer pouches, and the subject to long term stability tests at 40 ± 2°C (75 ± 5% R.H.) in accordance with the International Committee on Harmonization. After 6 to 8 weeks of storage under these “accelerated storage” conditions, atropine and tropic acid levels were analyzed by HPLC (UV-detection): The average amount of tropic acid formed from hydrolysis of the atropine was (Mean ± Std.Dev.) 1.6 ± 0.9%. These results can be extrapolated, that all atropine ophthalmic formulations as prepared will have a shelf life of at least 18 months when stored at standard conditions not exceeding 25°C.

Example 8 (non-inventive): Common Eye Drop Containers and Formulations

Five commercially available eye drop dispensers each containing a ready-to-use low- dose (0.01%) atropine ophthalmic formulation have been examined. The results are listed in Table 3 and Table 4. Drop volumes were assessed by gravimetry.

The variations in chemical and physical properties in the currently available formulations and containers are remarkable, in particular if taken into account the variability in the volume of a single drop, and thus of the dosage of drug dispensed each drop, which may well vary by a factor of 4 to 5 (Table 4), there is, admittedly, to date no clear controlled dosing of the atropine compound available. The definition of the atropine dose by means of the mere atropine concentration (e.g. 0.01% or 0.025%) falls short in light of the factual situation.

Table 3

Table 4

(EDO = single-dose container)

Claims

1. A ready-to-use topical ophthalmic formulation, comprising a buffered aqueous solution and from about 0.001 wt% to about 0.025 wt% of a long-lasting mydriatic, selected from atropine and a pharmaceutically acceptable salt, derivative or prodrug thereof, for use in a method of treatment of a condition of visual impairment caused by opacities and/or floaters of the vitreous in subject’s eye suffering from this condition, the method of treatment comprising the step of : topically administering the ophthalmic formulation to said eye in an amount such that the absolute pupil constriction amplitude of said eye’s pupillary light reflex to changes from a mesopic illuminance level to a photopic illuminance level is not less than 1.5 mm and not more than 4 mm.

2. The ophthalmic formulation of claim 1 , wherein said the absolute pupil constriction amplitude of said eye’s pupillary light reflex is from 2.0 mm to 4.0 mm for subjects having an age of less than 45 years and from 1.5 mm to 3.0 mm for subjects having an age of 45 years or more at the time of said treatment.

3. The ophthalmic formulation of claim 1 or 2, the method of treatment comprising the step of: topically administering an ophthalmic formulation comprising a long-lasting mydriatic to said eye in an amount such that the drug induced increase in pupil diameter of said eye at a photopic illuminance level after the administration of said ophthalmic formulation is not less than 1.0 mm and not more than 2.5 mm above said eye’s pupil diameter before the administration of said ophthalmic formulation.

4. The ophthalmic formulation of any one of the preceding claims, the method of treatment comprising the step of: topically administering the ophthalmic formulation to said eye in an amount such that the average pupil constriction amplitude of said eye’s pupillary light reflex to changes from a mesopic illuminance levels to photopic illuminance levels after the administration of said ophthalmic formulation is reduced to at least 60% and to not less than 30% of the average pupil constriction amplitude of said pupillary light reflex before the administration of said ophthalmic formulation.

5. The ophthalmic formulation of any one of the preceding claims, wherein said eye’s pupillary diameter and/or pupillary light reflex as after administration of the ophthalmic formulation are assessed from 1 hour to 4 hours after the topical administration of said amount the ophthalmic formulation to said eye.

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6. The ophthalmic formulation of any one of the preceding claims, wherein the mesopic illuminance level is about 1 to 3 cd/m² and the photopic illuminance level is about 100 to 250 cd/m².

7. The ophthalmic formulation of any one of the preceding claims, the method being further characterized in that said amount the ophthalmic formulation is administered to said eye each treatment day in a one-time dose at the beginning of daytime only.

8. The ophthalmic formulation of any one of the preceding claims, comprising the long lasting mydriatic at a concentration of from 0.005 to 0.01% (w/w).

9. The ophthalmic formulation of any one of the preceding claims, further comprising ascorbic acid and/or a pharmaceutically acceptable salt thereof.

10. The ophthalmic formulation of any one of the preceding claims, further comprising one or more cardenolide glycoside compounds, selected from Digitalis purpurea leaf extract and Digitalis lanata leaf extract.

11. The ophthalmic formulation of any one of the preceding claims, having a citric acid-based pH-buffering system at a concentration of from 2 mmol/L to 6 mmol/L citric acid and the ophthalmic formulation having a pH of less than 4.90 or less than pH 4.85.

12. The ophthalmic formulation of any one of the preceding claims, which is free of any preservative and detergent.

13. The ophthalmic formulation of any one of the preceding claims, which is free of any macromolecular viscosity modifier.

14. A kit for use in a treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous in the subject’s eye, comprising:

- an eye drop container or dispenser, containing an ophthalmic formulation which comprises from about 0.001 to about 0.025% (w/w) atropine or a pharmaceutically acceptable salt thereof or as characterized in any one of claims 8 to 13; and

35 - instructions for use to establish the subject’s individual treatment dose, comprising the steps of the method of treatment as characterized in any one of claims 1 to 7.

15. The kit of claim 14, further comprising:

- a medical device for establishing a subject’s individual pupil light reflex, the device being specifically designed in carrying out the steps of the method as characterized in any one of claims 1 to 5.

16. A method of determining a subject’s individual dose of a topical ophthalmic formulation, comprising a buffered aqueous solution and from about 0.001 wt% to about 0.025 wt% of a long-lasting mydriatic, selected from atropine and a pharmaceutically acceptable salt thereof, for use in a treatment to ameliorate a subject’s visual impairment caused by opacities and/or floaters of the vitreous in the subject’s eye, the method comprising the steps of:

- topically administering the ophthalmic formulation to said eye in an amount such that the average pupil constriction amplitude of said eye’s pupillary light reflex to changes from a mesopic illuminance levels to photopic illuminance levels after the administration of said ophthalmic formulation is reduced to at least 60% and to no less than 30% of the average pupil constriction amplitude of said pupillary light reflex before the administration of said ophthalmic formulation.

17. The method of claim 16, comprising the steps of:

- initially assessing the average pupil constriction amplitude of said eye’s pupillary light reflex to changes from a mesopic illuminance level to a photopic illuminance levels before administration of the ophthalmic formulation and storing the subject’s average pupil constriction amplitude as the reference level (100%);

- topically administering an initial predetermined dose of the ophthalmic formulation to said eye;

- consecutively assessing the average pupil constriction amplitude of said eye’s pupillary light reflex to changes from a mesopic illuminance level to a photopic illuminance level after administration of said initial dose and storing the subject’s average pupil constriction amplitude as the induced level;

- calculating the subject’s individual reduction of average pupil constriction amplitude as a fraction of said induced level by said initial dose and said reference level. The method of claim 17, further comprising the steps of:

- entering the individual level of reduction of the average pupil constriction amplitude and said initial dose amount into a lookup-table and retrieving from the look-up table a result, selected from an indication of an individual treatment dosage regimen and an indication to increase or decrease or maintain said initial dose; and

- outputting or displaying said result to the user.

9. The method of claim 18, wherein the look-up table comprises: