Systems and methods for monitoring ophthalmic drugs

Abstract

A system and method for monitoring / measuring the receptor action / blockade and intraocular penetration / concentration levels of an ophthalmic drug and determining an optimal treatment regimen based on the receptor action / blockade and intraocular penetration / concentration levels of the ophthalmic drug.

Description

[0001] Introduction

[0002] This disclosure generally relates to a system and method for monitoring / measuring the receptor action / blockade and intraocular penetration / concentration levels of ophthalmic drugs and determining an optimal treatment regimen based on the receptor action / blockade and intraocular penetration / concentration levels of the ophthalmic drugs. More specifically, this disclosure relates to a system and method for monitoring / measuring the receptor action / blockade and intraocular penetration / concentration levels of antimuscarinic drugs and determining an optimal myopia treatment regimen based on the receptor action / blockade and intraocular penetration / concentration levels of the antimuscarinic drugs. Background Art

[0003] Applying the anti-muscarinic ophthalmic drug atropine as an eye drop at a concentration of 0.5%-1.0% is the most effective treatment found so far for preventing myopia progression (Huang, J., Wen, D., Wang, Q., McAlinden, C., Flitcroft, I., Chen, H.,... Qu, J. (2016). Efficacy comparison of 16 interventions for myopia control in children: A network meta-analysis [Efficacy comparison of 16 interventions for myopia control in children: A network meta-analysis]. Ophthalmology [Ophthalmology], 123(4), 697-708). A study first published in Singapore in 2012 (ATOM2 Study [ATOM2 Study], Chia, A., Chua, W.-H., Cheung, Y.-B., Wong, W.-L., Lingham, A., Fong, A. and Tan, D. (2012). Atropine for the Treatment of Childhood Myopia: Safety and Efficacy of 0.5%, 0.1%, and 0.01% Doses (Atropine for the Treatment of Myopia 2) [Atropine for the Treatment of Childhood Myopia: Safety and Efficacy of 0.5%, 0.1%, and 0.01% Doses (Atropine for the Treatment of Myopia 2)]. Ophthalmology [Ophthalmology], 119(2), 347-354) showed that very low doses (i.e., 0.01%) of atropine applied to the eye in the form of eye drops were almost as effective as the standard dose (1.0%) in slowing myopia progression. The interest in low-dose atropine lies in the fact that the standard dose of atropine causes pupil dilation and accommodation (near focusing) paralysis through its antagonistic action on the muscle protein receptors in the eye, which can last up to 7 days. These effects on the pupil and accommodation system are the main uses of atropine, but in terms of the treatment of myopia progression, these may be regarded as side effects that limit the use of atropine in myopia control.At 0.01%, the side effects on pupil size and accommodation are minimal and undoubtedly tolerable for most subjects (Loughman, J. and Flitcroft, D.I. (2016). The acceptability and visual impact of 0.01% atropine in a Caucasian population [0.01% atropine in the Caucasian population's acceptability and visual impact]. British Journal of Ophthalmology [British Ophthalmology Journal], 100(11), 1525-1529), but in the longest low-dose atropine clinical trial to date (the ATOM2 study), this concentration has been shown to be effective in slowing myopia progression.

[0004] This has generated great interest in the use of 0.01% atropine eye drops as a treatment for preventing myopia progression. There is also controversy over whether 0.01% atropine is truly effective, as some follow-up studies (e.g., the LAMP study in Hong Kong, Yam, J.C., Jiang, Y., Tang, S.M., Law, A.K.P., Chan, J.J., Wong, E.,... Pang, C.P. (2019). Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control [Low-concentration atropine for myopia progression (LAMP) study: A randomized, double-blind, placebo-controlled trial of 0.05%, 0.025%, and 0.01% atropine eye drops in myopia control]. Ophthalmology [Ophthalmology], 126(1), 113-124) found little effect on eye growth. These same studies also found that side effects are minimal at the lowest dose, and that as the atropine concentration increases, effectiveness increases and side effects increase.

[0005] One challenge with atropine formulations is that atropine is not very stable in solutions at physiological pH levels (i.e., near 7.0). This results in a potential for the formulation to be unstable, and thus the relative lack of efficacy of the customized formulation may be due to loss of the active drug over time. Another challenge with such low doses is that the variability of penetration into the eye (i.e., where the drug exerts its effect) can affect efficacy. Additionally, atropine and other antimuscarinic drugs are limited by melanin, which is present in variable amounts in different colored eyes, and this affects the amount of drug reaching the muscarinic receptors. These variables mean that in subjects without side effects, the amount of drug reaching the receptors may be ineffective. In such cases, higher concentrations or more frequent administrations would be appropriate to ensure a therapeutically effective dose is achieved within the eye.

[0006] For most topical drug ocular administrations, and when using atropine to dilate the pupil, the aim is to achieve maximum target receptor blockade for maximum effect. In the case of low atropine doses (e.g., in the range of 0.01% to 0.1%), achieving acceptable low levels of side effects such as photophobia (caused by increased pupil size) and loss of near reading ability (caused by loss of accommodation) only requires partial blockade of the receptors under consideration.

[0007] Both pupil size and accommodation are controlled by feedback loops where changes in the light level reaching the retina or retinal blur signals cause the eye to respond, and the response is used to reduce the imposed light level changes by altering pupil size or to minimize retinal blur by changing the focusing distance of the eye.

[0008] However, the prior art only allows measurement of both the pupil size and the accommodation level of the eye in terms of static and dynamic measurements, as it is unacceptable to take samples from a living eye to measure the drug level in the eye due to risks such as infection. Thus, the known techniques can simply measure the overall response from the pupil light and accommodation control systems without attempting to determine or estimate internal factors such as the degree of operation of the effector muscles in the pupil and ciliary body. Pupil size can be measured by infrared pupillometry, where infrared light is shone into the eye and the amount of light reflected back through the pupil is measured to determine the pupil area and thus the diameter. For example, WO 2011 / 016029 A2 describes a conventional pupillometer for performing a visual field test on an individual. Pupillometry can also be achieved by image analysis of high-speed video of the anterior segment of the eye.

[0009] The adjustment can also be dynamically measured using an adjustment measuring device, such as a system that dynamically measures based on the Sheiner principle, a retinoscope system, optimal focusing of a retinal image, or the principle of light deflection. A device for determining the eye position and the direction of gaze (e.g., Maddox wing, limbal eye tracker, or video eye tracker) can be used to measure accommodative convergence. The accommodative convergence ratio (AC / A) can be determined based on the ratio of this accommodative convergence response to the accommodative stimulus or the accommodative response.

[0010] However, existing devices for measuring pupil size and accommodation are only configured to monitor these functions related to normal function or in the presence of disease, rather than being optimized to monitor the muscarinic receptor blockade level or the intraocular penetration / concentration level of an antimuscarinic drug in order to determine the optimal myopia treatment plan for a patient.

[0011] In short, current techniques for measuring pupil size and accommodation only measure the end results of two complex feedback loops, and the effects of the feedback loops mask the effects of partial receptor blockade of the type that needs to be monitored when using drugs such as antimuscarinic drugs. Most antagonist drugs act in a competitive manner, i.e., their blocking effects vary with the concentrations of both the drug and the agonist (which can usually be a physiological neurotransmitter). Therefore, the term "receptor blockade" in this context represents the degree to which an antagonist drug blocks an intraocular physiological function, and this blockade in turn affects the neural pupil or the operation of the accommodation or accommodative convergence control system operating in the brain in a more complex and non-linear manner. In addition, since the effect of atropine on eye growth may take a year or more to determine, and the rapid and obvious side effects of low-dose atropine only exist in a small subset of subjects, this raises the need for measuring devices and techniques for determining how much atropine reaches the muscarinic receptors in the eye.

[0012] In summary, while current devices and methods measure pupil size and accommodation, they are not configured to extract appropriate parameters, and furthermore, they are unable to extract appropriate parameters to best estimate the degree of receptor blockade in the pupil or ciliary muscle caused by the administration of antimuscarinic agents such as atropine and related drugs. Known devices and methods are also not adapted to process these parameters in a manner conducive to measuring the intraocular penetration / concentration of antimuscarinic drugs, and known devices or methods are also unable to determine the optimal myopia treatment plan based on the receptor action and intraocular penetration / concentration level of antimuscarinic drugs.

[0013] Therefore, an object is to overcome at least some of the problems of the prior art. SUMMARY OF THE INVENTION

[0014] According to the present invention, there is provided a method and a system for monitoring the intraocular concentration level of an ophthalmic drug in a patient, as set forth in the appended claims, the system comprising:

[0015] A testing device for testing the pupillary response or accommodation response to the ophthalmic drug, the device being configured to test the patient to extract data regarding the pupillary response or accommodation response, and the system being configured to:

[0016] Estimate the intraocular concentration of the drug based on the extracted data.

[0017] Preferably, the intraocular concentration is estimated by calculating at least one data parameter value and comparing it with a reference database of known data parameters.

[0018] Advantageously, at least one data parameter is calculated from the open-loop phase of the pupillary or accommodation response.

[0019] Preferably, the at least one data parameter includes: the maximum change in pupil diameter from baseline, the size change at 2x latency, the pupil velocity at 2x latency, the average velocity up to 2x latency, the peak velocity up to and including the 2x latency point, and the area under the curve at 2LP.

[0020] Alternatively or additionally, the at least one data parameter includes accommodation or accommodative convergence parameters.

[0021] Preferably, the level of receptor blockade caused by the ophthalmic drug is estimated by comparing the at least one data parameter with a reference database including the patient's pre-treatment baseline.

[0022] Alternatively, the level of receptor blockade caused by the ophthalmic drug is estimated by comparing the at least one data parameter with a reference database including a normative database or reference group data.

[0023] Preferably, the intraocular concentration level of the ophthalmic drug is calculated based on the estimated level of receptor blockade.

[0024] Advantageously, the system further includes the step of determining an optimal treatment regimen based on the intraocular concentration of the ophthalmic drug. Suitably, the system includes the step of evaluating whether the calculated intraocular concentration is within the therapeutic range.

[0025] Additionally, the system includes: determining the ratio of the calculated intraocular concentration to the desired intraocular concentration and calculating the dose or dosing frequency accordingly, and subsequently includes the step of adjusting the dose as needed.

[0026] In a preferred embodiment, the drug is an antimuscarinic drug. Preferably, the antimuscarinic drug is selected from the group consisting of: atropine, homatropine, cyclopentolate, tropicamide, hyoscyamine, and scopolamine. Optionally, the treatment regimen is a myopia treatment regimen.

[0027] In one embodiment, the test device includes a pupillometer. Preferably, the pupillometer includes:

[0028] a stimulation / test chamber;

[0029] a short wavelength visible light source; and

[0030] a long wavelength light source, wherein the long wavelength light source is configured to be activatable for a duration less than or equal to the latency of the eye pupil response.

[0031] Suitably, the pupillometer includes a step or pulse function to activate the long wavelength light source for a duration less than or equal to the latency of the eye pupil response.

[0032] Advantageously, the short wavelength visible light source is configured to be permanently on during monitoring.

[0033] In another embodiment, the test device includes an accommodation or accommodative convergence measuring device.

[0034] Preferably, the test device includes a controller for controlling and recording stimulation control, data acquisition, storage, and analysis functions. Advantageously, the controller includes a computer.

[0035] The present invention also extends to a method of monitoring the intraocular concentration level of an ophthalmic drug in a patient, the method comprising: testing the patient with a test device to extract data regarding pupil response or accommodation response, and estimating the intraocular concentration of the drug based on the extracted data.

[0036] Suitably, the intraocular concentration is estimated by calculating at least one data parameter value and comparing it with a reference database of known data parameters.

[0037] Preferably, at least one data parameter is calculated from the open-loop phase of the pupil or accommodation response. In one embodiment, the at least one data parameter includes: the maximum change in pupil diameter from baseline, the size change at 2x latency, the pupil velocity at 2x latency, the average velocity up to 2x latency, the peak velocity up to and including the 2x latency point, and the area under the curve at 2LP.

[0038] Alternatively, the at least one data parameter includes an accommodation or accommodative convergence parameter.

[0039] Preferably, the receptor blockade level caused by the ophthalmic drug is estimated by comparing the at least one data parameter with a reference database including the patient's pre-treatment baseline.

[0040] Alternatively or additionally, the level of receptor blockade caused by the ophthalmic drug is estimated by comparing the at least one data parameter to a reference database comprising a normative database or a reference set of data.

[0041] Preferably, the intraocular concentration level of the ophthalmic drug is calculated based on the estimated receptor blocking level.

[0042] Suitably, the method further comprises the step of determining an optimal treatment regimen based on the intraocular concentration of the ophthalmic drug.

[0043] Advantageously, the method comprises evaluating whether the calculated intraocular concentration is within the therapeutic range.

[0044] Preferably, the method comprises determining the ratio of the calculated intraocular concentration to the desired intraocular concentration and calculating the dosage or dosing frequency accordingly.

[0045] Suitably, the method further comprises the step of adjusting the dosage as required.

[0046] In preferred embodiments of the methods of the present invention, the drug is an antimuscarinic drug.

[0047] Preferably, the antimuscarinic drug is selected from the group consisting of atropine, homatropine, cyclopentolone, tropicamide, hyoscyamine and scopolamine.

[0048] Optionally, the treatment regimen is a myopia treatment regimen.

[0049] In one embodiment, the method further comprises the step of smoothing the data using a filter.

[0050] In another embodiment, the present invention further comprises the step of performing machine learning based on the data obtained from the patient.

[0051] In another embodiment, the present invention also extends to a computer-implemented method of treating a patient with an ophthalmic medication, the method comprising:

[0052] testing the patient with a testing device to extract data regarding pupillary or accommodative responses, and

[0053] The intraocular concentration of the drug is estimated based on the extracted data to monitor the intraocular concentration level of the ophthalmic drug in the patient.

[0054] Suitably, the intraocular concentration is estimated by calculating at least one data parameter value and comparing with a reference database of known data parameters.

[0055] Preferably, at least one data parameter is calculated from the open-loop phase of the pupil or accommodation response. In one embodiment, the at least one data parameter includes: maximum change in pupil diameter from baseline, change in size at 2x latency, pupil velocity at 2x latency, average velocity up to 2x latency, peak velocity up to and including 2x latency, and area under the curve at 2LP.

[0056] Alternatively, the at least one data parameter comprises a regulation or regulation set parameter.

[0057] Preferably, the level of receptor blockade caused by the ophthalmic drug is estimated by comparing the at least one data parameter to a reference database comprising a pre-treatment patient baseline.

[0058] Alternatively or additionally, the level of receptor blockade caused by the ophthalmic drug is estimated by comparing the at least one data parameter to a reference database comprising a normative database or a reference set of data.

[0059] Preferably, the intraocular concentration level of the ophthalmic drug is calculated based on the estimated receptor blocking level.

[0060] Suitably, the method further comprises the step of determining an optimal treatment regimen based on the intraocular concentration of the ophthalmic drug.

[0061] Advantageously, the method comprises evaluating whether the calculated intraocular concentration is within the therapeutic range.

[0062] Preferably, the method comprises determining the ratio of the calculated intraocular concentration to the desired intraocular concentration and calculating the dosage or dosing frequency accordingly.

[0063] Suitably, the method further comprises the step of adjusting the dosage as required.

[0064] In preferred embodiments of the methods of the present invention, the drug is an antimuscarinic drug.

[0065] Preferably, the antimuscarinic drug is selected from the group consisting of atropine, homatropine, cyclopentolone, tropicamide, hyoscyamine and scopolamine.

[0066] Optionally, the treatment regimen is a myopia treatment regimen.

[0067] In one embodiment, the method further comprises the step of smoothing the data using a filter.

[0068] In another embodiment, the present invention further comprises the step of performing machine learning based on the data obtained from the patient.

[0069] The present invention also relates to a device for monitoring intraocular penetration and / or receptor action levels of an ophthalmic drug, the device comprising:

[0070] stimulation / test chambers;

[0071] a short wavelength visible light source configured to accommodate light; and

[0072] A long wavelength light source as a stimulus, wherein the long wavelength light source is configured to be activatable for a duration less than or equal to a latency of a pupillary response of the eye.

[0073] Preferably, the device further comprises an infrared light source.

[0074] In a preferred embodiment, the device comprises a step or pulse function that activates the long wavelength light source for a duration that is less than or equal to the latency of the pupillary response of the eye.

[0075] Preferably, the device comprises an infrared detector. More preferably, the infrared detector comprises a camera or a photodiode.

[0076] Advantageously, the apparatus further comprises a beam splitter for illuminating the retina along the visual axis with infrared light from the light source. Preferably, the beam splitter comprises a half-silvered mirror. More preferably, the beam splitter is co-aligned with the infrared detector.

[0077] Preferably, the short-wavelength visible light source emits visible light having a wavelength of about 440 nm to about 480 nm.

[0078] Preferably, the long wavelength light source emits light having a wavelength of about 550 nm to about 640 nm.

[0079] Suitably, the short wavelength visible light source is configured to be permanently switched on during monitoring.

[0080] In one embodiment, the light source comprises a light emitting diode.

[0081] Preferably, the stimulation / test chamber comprises a Ganzfeld chamber. More preferably, the stimulation / test chamber comprises a highly reflective coating for defining the Ganzfeld chamber.

[0082] Suitably, the stimulation / test chamber comprises an eye cup for receiving an eye.Preferably, the eye cup defines an optical seal.

[0083] In an alternative embodiment, the apparatus comprises a Maxwell imaging system.

[0084] Suitably, the short wavelength visible light source and the long wavelength light source are imaged into an artificial pupil.

[0085] In one embodiment, the device is a monocular device. Alternatively, the device is a binocular device.

[0086] Preferably, the device further comprises a controller for controlling and recording stimulation control, data acquisition, storage and analysis functions. More preferably, the controller comprises a computer.

[0087] The present invention also extends to a computer-implemented method of monitoring intraocular penetration and / or receptor blockade levels of a drug, the method comprising: applying short wavelength visible light and long wavelength light to the eye, wherein the long wavelength light is applied for a duration less than or equal to the latency of the pupillary response of the eye.

[0088] Preferably, the long wavelength light is activated by a step or pulse function.

[0089] Advantageously, the long wavelength light is also applied for a duration of about twice the latency of the eye's pupil response.

[0090] Preferably, the short wavelength adapting light is applied for at least two minutes.

[0091] Suitably, the long wavelength light has a wavelength of about 550 nm to about 640 nm.

[0092] Preferably, the short wavelength visible light is activated first. More preferably, the short wavelength visible light is permanently turned on during the monitoring period.

[0093] Suitably, the short wavelength light is activated in pulses of 200 milliseconds or longer. Preferably, the short wavelength visible light has a wavelength of about 440 nm to about 480 nm so as to photoadapt certain classes of photoreceptors (rods and short wavelength sensitive cones) and other photosensitive retinal cells (e.g., intrinsically photosensitive retinal ganglion cells ipRGCs).

[0094] Preferably, the present invention further comprises the step of extracting the pupil diameter at each time point from a video or photoelectric sensor.

[0095] Advantageously, the method further comprises the step of smoothing the data with a filter to estimate the first derivative of the pupil diameter.

[0096] In one embodiment, the present invention further includes the step of calculating at least one of the following: the maximum change in pupil diameter from baseline, the change at 2x latency (approximately 400 milliseconds) from the start of long wavelength stimulus light, the pupil velocity at 2x latency (approximately 400 milliseconds), the average velocity from a time point (i.e., latency) until 2x latency, and the peak velocity up to and including the 2x latency time point.

[0097] Preferably, the method further comprises: calculating a numerical integral of the change in pupil size from baseline to the 2x latency time point.

[0098] Suitably, the method further comprises: calculating the ratio of the observed parameter to the pre-treatment baseline value of the patient, age-matched normative data, or reference group data to estimate the level of functional block in the receptor iris.

[0099] In a preferred embodiment, the invention further comprises: calculating the treatment required for the desired receptor block.

[0100] Preferably, the drug is an antimuscarinic drug. More preferably, the antimuscarinic drug is selected from the group consisting of: atropine, homatropine, cyclopentolate, tropicamide, hyoscyamine, and scopolamine.

[0101] Suitably, the method further comprises: performing a step of machine learning based on the data obtained from the patient.

[0102] Preferably, the method further comprises: a step of changing the concentration of the drug or changing the application frequency to the eye in response to data obtained by monitoring the intraocular penetration and / or receptor block level of the drug. More preferably, the concentration of the drug is changed by adjusting the size of the eye drop containing the drug. Most preferably, the eye drop comprises a fixed-concentration eye drop with a varying viscosity. Alternatively, the concentration is changed by the dynamic mixing of the drug active ingredient and the placebo.

[0103] Preferably, the mixing is performed by an electric device employing a drop-on-demand delivery system.

[0104] Suitably, the method further comprises: performing a pharmacological challenge with a high dose of a suitable agonist that acts on the same receptor as the test drug to provide a direct assessment of the receptor block.

[0105] In another embodiment, the invention also extends to a method of treating a patient with an ophthalmic drug, the method comprising using a device as defined above.

[0106] The invention also extends to a method of treating a patient with an ophthalmic drug, the method comprising using a method of monitoring intraocular penetration and / or receptor block level as defined above.

[0107] In a preferred embodiment of the treatment method, the drug is an antimuscarinic drug.

[0108] In another embodiment, there is provided a system and a computer-implemented method for monitoring the intraocular concentration level of an ophthalmic drug in a patient, the system comprising:

[0109] A test device for testing the pupillary or accommodation response to an ophthalmic drug, the device being configured to test a patient to extract data regarding the response of the pupillary control system or the accommodation control system to visual stimuli, wherein the system is configured to:

[0110] Determine the degree of action of the ophthalmic drug on intraocular receptors in the iris and / or ciliary muscle tissue based on the extracted data; and

[0111] Estimate the intraocular concentration of the drug based on the calculated degree of action on the intraocular receptors.

[0112] Thus, the system and method of the present invention combines the measurement of eye response parameters (of pupil, accommodation, and / or accommodative convergence) with an algorithm that optimizes the estimation of intraocular drug concentration based on the receptor blockade level. For example, at a 1% concentration in an eye drop, it can be calculated what the degree of binding at the receptor should be, and by estimating the observed intraocular receptor binding, the intraocular concentration can be calculated and thus the effective drug penetration can be calculated.

[0113] Thus, the present invention is capable of identifying measurable aspects of the pupillary and accommodation responses (including accommodative convergence measurements for the purposes of this application), which can estimate receptor blockade without being affected by the feedback nature of the control systems involved and other physiological factors that may affect both pupil size and accommodation. These parameters can then be integrated into treatment methods, assessment, and monitoring programs to ensure that the treatment method provides optimal efficacy over time regardless of any receptor upregulation or downregulation and with minimal side effects.

[0114] Thus, the present invention helps to estimate the percentage of receptor blockade of muscarinic receptors in the eye of a living subject in a clinically acceptable manner during treatment. This is particularly beneficial for the treatment of children, who make up the majority of patients in need of treatment for progressive myopia.

[0115] The present invention helps to monitor over time any possible upregulation of muscarinic receptors (due to irreversible receptor blockade by atropine) during treatment and any associated enhanced muscarinic response upon cessation of treatment. This is of particular interest because it has been found that upon cessation of treatment with high-dose (e.g., 1%) atropine for myopia, progressive myopia and accelerated eye growth rebound occur. Evidence of receptor upregulation provided by the devices and methods of the present invention allows for a slow reduction in treatment to prevent rebound eye growth upon cessation of treatment. Thus, the present invention also helps to avoid rebound progression of myopia by identifying the appropriate reduction in atropine concentration over time once it has been deemed appropriate to stop treatment.

[0116] The systems and methods of the present invention can be used for patient monitoring, where the patient is being treated with any topical preparation that acts on the muscarinic receptors that control accommodation and / or pupil size. The devices of the present invention are particularly suitable for use in situations where the desired therapeutic intervention is only a partial blockade of such receptors. Examples of antimuscarinic agents suitable for use with the present invention include preparations of low-dose atropine, homatropine, cyclopentolate, tropicamide, hyoscyamine, and scopolamine.

[0117] A computer program is also provided, which includes program instructions for causing a computer program to execute the above method, and the computer program can be implemented on a recording medium, a carrier signal, or a read-only memory. BRIEF DESCRIPTION OF THE DRAWINGS

[0118] The present invention will now be described by way of example only with reference to the drawings and examples, in which:

[0119] Figure 1 is a schematic representation of a pupillary light reflex feedback loop system;

[0120] Figure 2 is a schematic representation of a double interactive feedback loop for accommodation and vergence, where AS and VS = accommodation and vergence demands, AR and VR = accommodation and vergence responses, Acg and Vcg = gains of the accommodation and vergence controllers, and Abias and Vbias = resting or tonic levels of accommodation and vergence, Ca = gain of the convergence-accommodation crosslink, and Ac = gain of the accommodation-convergence crosslink;

[0121] Figure 3 is a representation of the standard parameters of the dynamic pupillary light response 1) maximum pupil diameter, 2) minimum pupil diameter, 3) pupil constriction rate, 4) constriction latency, 5) average constriction velocity, 6) maximum constriction velocity;

[0122] Figure 4 is a flowchart of a first embodiment of a system and method for monitoring / measuring the receptor action and intraocular penetration / concentration level of an antimuscarinic drug and determining an optimal myopia treatment regimen based on the receptor action and intraocular penetration / concentration level of the antimuscarinic drug;

[0123] Figure 5 is similar to Figure 4 but a flowchart of a second embodiment of the system and method of the present invention in which a normative database is employed;

[0124] Figure 6 is Figure 4 and Figure 5a flow chart of data analysis performed on data in a system and method for treating a patient with a drug, wherein a measurement algorithm estimates an effective intraocular concentration of a drug at a site of action, and a treatment decision algorithm determines a ratio of the estimated dose to an ideal dose and calculates an optimal dose and / or dosing frequency to achieve a therapeutic concentration;

[0125] Figure 7 is a schematic representation of a clinical measurement apparatus / device adapted for monitoring intraocular penetration and receptor blockade levels of a topical drug positioned adjacent to an eye (not drawn to scale) using open-loop operation of the pupillary light reflex;

[0126] Figure 8 is a schematic representation of an alternative embodiment of a clinical measurement apparatus in which a Maxwell imaging system is employed;

[0127] Figure 9 is a graph of pupillary responses before and after low-dose atropine treatment;

[0128] Figure 10 is a graph of pupil constriction velocity before and after low-dose atropine treatment;

[0129] Figure 11 It is a schematic representation of the regulation collective control model when the collective system is open-loop;

[0130] Figure 12 is a graph of the percent change in AC / A ratio for different patients; and

[0131] Figure 13 Figure 2 is a dose adjustment curve for a target receptor blockade of 0.35. DETAILED DESCRIPTION

[0132] The present invention enables the identification of measurable aspects of pupillary and accommodative responses that can estimate receptor blockade independent of the feedback loops of the control systems involved and other physiological factors that may affect both pupil size and accommodation. Thus, as discussed further below, the present invention provides a system and method for monitoring / measuring the receptor effects and intraocular penetration / concentration levels of antimuscarinic drugs and determining an optimal myopia treatment regimen based on the receptor effects and intraocular penetration / concentration levels of the antimuscarinic drugs.

[0133] Figure 1 A schematic representation of a prototype feedback pupil light control loop system 1 is shown with input 2, which for the pupil light reflex is the light intensity controlled in feedback loop 1 by changes in pupil diameter and therefore area. The activity that needs to be isolated in this system to estimate receptor blockade is facility 3, which represents the smooth muscle of the pupillary sphincter and its muscarinic receptors.

[0134] Figure 2A schematic diagram of the dual reciprocal feedback loops of accommodation 4 and vergence 5 is shown, where AS and VS = accommodation and vergence demands, AR and VR = accommodation and vergence responses, Acg 6 and Vcg 7 = gains of the accommodation and vergence controllers, Abias 8 and Vbias 9 = resting or tonic levels of accommodation and vergence, Ca 10 = gain of the convergence-accommodation cross-link, and Ac 11 = gain of the convergence-accommodation cross-link. As shown, the accommodation control system is even more complex than the pupillary light reflex system 1 due to the interaction between the closed-loop focus system 4 and the convergence loop control system 5 to align the axes of the two eyes for objects at different distances. In this system, low-dose antimuscarinics are used to alter the accommodation response by reducing the amount of ciliary muscle contraction, resulting in changes in lens shape and, therefore, accommodation.

[0135] If the receptors involved at the level of the smooth muscles in the pupil and ciliary body (which control accommodation) are completely blocked (or nearly completely blocked), no output response is observed, as is the case with a full dose of atropine. If only a certain percentage of the receptors are blocked, the stimulus driving the response will be less effective and less rapidly attenuated, and the control mechanism will be activated for a longer period of time until the system achieves a maximum response. The feedback nature of both the pupil and accommodation control systems means that the final response may be only slightly attenuated, even if 10% or 25% of the receptors are blocked.

[0136] As indicated above, static pupillometry measures pupil size at a given lighting level. This is subject to diurnal variation and is influenced by a range of autonomic and psychological factors, as well as factors such as dietary intake of caffeine, for example. Figure 3 The standard parameters of the dynamic pupillary light response are: 1) maximum pupil diameter, 2) minimum pupil diameter, 3) pupil constriction rate, 4) constriction latency, 5) mean constriction velocity, and 6) maximum constriction velocity. As shown in the figure, a series of parameters for dynamic pupillary responses is described, measuring the change in pupil diameter over time after the presentation of a bright light stimulus. These dynamic accommodation measures are rarely used in clinical practice and are generally considered only as research tools.

[0137] Thus, known systems, devices, and methods for measuring pupil size and accommodation are configured only to monitor these functions in relation to normal function or in the presence of disease, rather than to monitor muscarinic receptor blockade and intraocular penetration / concentration levels in the presence of antimuscarinic drugs. Consequently, these methods and devices do not aid in determining optimal myopia treatment regimens based on the receptor effects and intraocular penetration / concentration levels of antimuscarinic drugs.

[0138] As indicated above, the present invention addresses these deficiencies.

[0139] Figure 4A flow chart illustrating a first embodiment of a system and method for monitoring / measuring receptor effects and intraocular penetration / concentration levels of an antimuscarinic drug and determining an optimal myopia treatment regimen based on the receptor effects and intraocular penetration / concentration levels of the antimuscarinic drug.

[0140] As shown, at the beginning 100 of the method of the present invention, a method is first performed using a method such as that described in more detail below. Figure 7 and Figure 8 A patient is tested 101 using a clinical measurement device / equipment, such as a device 12. Receptor function parameters are then extracted from the raw data 102, and baseline measurements of the receptor function parameters are then obtained 103. The baseline data may include data from different eye colors, as the amount of pigment in the eye is known to affect the effect of intraocular muscarinic topical medications. The baseline measurements are then stored in a reference database 104. Treatment of the patient is then initiated 105, and the patient is subsequently retested using the clinical measurement device 106, and receptor function parameters are again extracted from the raw data 107. Measurements of the receptor function parameters are then obtained 108, and receptor blockade is determined by comparing the receptor function parameters to the baseline data in the reference database 104 to estimate intraocular drug concentration 109.

[0141] An assessment is then performed to determine whether optimal therapeutic intraocular drug levels have been achieved 110. If optimal therapeutic intraocular drug levels have been achieved, treatment is continued 111 and a follow-up visit (usually within 2 to 6 months) is scheduled 112 for retesting 106. If optimal therapeutic intraocular drug levels have not yet been achieved, the dose / frequency required to bring levels into the optimal range is calculated based on the current receptor blockade level 113 (this is done in the Figure 13 A follow-up visit 114 is then scheduled (usually within 1 month) to determine if treatment needs further modification 105.

[0142] Figure 5 is similar to Figure 4 This is a flow chart of a second embodiment of the system and method of the present invention, but in which a normative database is used as a reference database. Like numbers indicate like components. More specifically, in this embodiment, after initiating or modifying treatment 105, conducting a test using a clinical measurement device 106, extracting receptor function parameters from the raw data 106, and measuring the function parameters 108, the normative database 115 is used to determine receptor blockade and estimate intraocular drug concentration 116 by comparing the receptor function parameters with the normative data. Optimal therapeutic drug levels are then queried 110, and subsequent actions are taken as previously described.

[0143] In another embodiment of the present invention, the receptor function parameters may be compared to a reference database comprising reference group data (ie, test data obtained from a reference group).

[0144] Figure 6 A flow chart illustrating the operation of the overall system and method of the present invention, which can be broken down into: a first step consisting of performing a test 117 using a clinical measurement device to extract raw test data; a second step 118, in which data analysis is performed on the data via a measurement algorithm to estimate the effective intraocular concentration of the drug at the site of action; and a third step 119, in which a treatment decision algorithm is used to determine the ratio of the estimated dose to the desired / ideal dose and calculate the optimal dose and / or dosing frequency to achieve a therapeutic concentration.

[0145] More specifically, in a first step 117 after starting the method 100 of the present invention, stimulation parameters are set in a test measurement device and recording of data is activated 120. The test measurement device may be a pupillometer, an accommodation measurement device, or a method for measuring accommodation set as described herein. For the purposes of this example, the test measurement device is a device such as Figure 7 and Figure 8 The pupil meter shown is a pupil meter, and the data is pupil size data. Raw pupil size data is extracted from the pupil meter, and then a mathematical smoothing filter 121 is applied to the data.

[0146] The smoothed data is then subjected to a second step 118, in which one or more desired parameters are calculated from the open-loop phase of the pupillary response (e.g., change in magnitude at two-fold latency (2LP), velocity at 2LP, average velocity up to 2LP, area under the curve at 2LP) 122. The proportion of receptor blockade is then estimated by comparing the desired open-loop parameters with normative data, pre-treatment baseline data from the patient, or reference group data as previously described 123. The effective intraocular concentration of the drug at the site of action is then estimated 124, as further described below.

[0147] A treatment decision is then made in the third step 119. More specifically, as outlined above, a query is then made as to whether the intraocular drug concentration is within the therapeutic range 125. If so, normal clinical monitoring continues 126. If not, the ratio of the estimated intraocular drug concentration to the ideal intraocular drug concentration is determined, and the dose or dosing frequency required to achieve the desired therapeutic concentration is calculated. The dose is then adjusted accordingly, as needed, and the patient is retested 128.

[0148] Method

[0149] In the systems and methods of the present invention, receptor blockade levels can be used to determine the bioavailability and effectiveness, compliance, and optimize / monitor the treatment regimen for a particular patient, and many of the steps now described can be performed in software or a processor module configured to execute program instructions to perform one or more of the following steps. Accordingly, the systems and methods of the present invention form the basis for a system that monitors drug levels in a living eye and adjusts treatment accordingly to obtain optimal results.

[0150] As, for example Figure 4 shown, a patient considered suitable for treatment is first subjected to a baseline assessment of pupil dynamics and / or accommodation function and / or accommodative-convergence by performing a test 101 using a clinical measurement device, which may be a pupillometer as described in more detail below.

[0151] Once treatment has commenced, repeated testing can be performed within a time window allowing sufficient time for intraocular penetration (a minimum of 15 minutes) and at any time during the treatment phase. Follow-up testing should be performed at comparable times of day or with a similar time interval between instilling the eye drops and testing receptor function. Baseline pupil size is also affected by ambient lighting, and for all measurements, the ambient lighting should be maintained at a similar level.

[0152] For a given patient, the upper limit of tolerance for side effects in terms of photophobia and loss of accommodation represents the maximum treatment level in terms of drug concentration or frequency of use. In cases where the patient does not experience significant side effects (most patients do not experience significant side effects with low-dose antimuscarinic treatment), the degree of receptor blockade is evaluated based on one or more of the oculomotor parameters, which may be the maximum change in pupil diameter from baseline, the change at 2x latency (approximately 400 milliseconds), the pupil velocity at 2x latency (approximately 400 milliseconds), the average velocity from a time point equal to the latency until 2x latency, and the peak velocity up to and including the 2x latency time point, see Figure 6 .

[0153] The concentration of the active drug can be increased by prescribing a higher concentration of the formulation or increasing the frequency of treatment, which typically starts at once daily. Conversely, if the patient is symptomatic, an estimate of the receptor blockade level allows prediction of an appropriate reduction in treatment.

[0154] The estimate of receptor blockade as a ratio or percentage (see Figure 6The measurement steps 122 to 124 in the flow chart allow for rational adjustment of the dosage. For example, if the level of receptor blockade is below the target level for optimal efficacy with minimal side effects, the concentration can be increased and then the level of receptor blockade reassessed. Conversely, if the patient experiences symptoms due to the effect of the formulation on pupil size and / or accommodation, the dose or frequency of administration can be adjusted downward.

[0155] Therapeutic changes can be best estimated by models based on the nonlinear relationship between the concentration of the drug and the amount of receptor bound. Typically, there is a sigmoidal relationship between receptor occupancy and the logarithm of the drug concentration. This can be expressed as the following equation:

[0156] [AR]=[A][RT] / ([A]+[KA])

[0157] Where AR is the amount of receptor bound by the drug, A is the drug concentration, KA = the apparent dissociation constant of the drug for the receptor (which is a well-characterized value for most drugs and has been measured to be 0.4-0.7 nM for atropine acting on human iris muscarinic receptors), and RT = the total number of receptors. This can be used to estimate the amount of bound receptors that will be obtained from a source eye drop (e.g., 0.01%, 0.02%, or 0.05% atropine). The same equation can be rearranged to then estimate the amount of ocular concentration / permeation based on the ratio of the applied concentration to the concentration calculated based on intraocular receptor binding.

[0158] The relationship between receptor blockade (expressed as a ratio from 0 to 1, i.e., percent blockade / 100) and drug concentration can be defined by the following relationship:

[0159] Receptor blockade (B) = ([AR] / [RT]) = [A] / ([A]+[KA])

[0160] and intraocular drug concentration = [KA].B / (1-B)

[0161] If the observed receptor blockade is B and the target ratio of receptor blockade is B T , then the ratio of the required intraocular drug concentration to the current drug concentration is given by the following formula:

[0162] The ratio of the required drug concentration to the current drug concentration = (B T (1-B) / (B(1-B T ))

[0163] Thus, if an estimated receptor blockade of 0.1 (or 10%) is achieved and the goal for optimal efficacy with minimal side effects is 0.35 (or 35%), the concentration in the eye should be increased by (0.35x(1 - 0.1)) / (0.1x(1 - 0.35)) = 4.85-fold. Conversely, if the initial treatment achieves an excessive level of receptor blockade that causes side effects (e.g., 0.90 or 90%), the appropriate concentration should be reduced to 0.06-fold of the original concentration to achieve a receptor blockade of 0.35 (35%). The specific ideal goal for achieving optimal myopia control for a given class of patients can be determined through clinical trials and then achieved in clinical practice through the present invention. For a given receptor blockade goal, the above equation can be plotted in graphical form to provide a physical dose adjustment calculator. As Figure 13 shown, the observed receptor blockade on the x-axis can be used to read the appropriate concentration adjustment on the y-axis.

[0164] Subsequent measurements can ensure that a sufficient level of receptor blockade is achieved at this new treatment level to obtain the desired therapeutic effect and eliminate the experienced side effects. A very important aspect of this method is that these adjustments can be made within a very short period after the start of treatment, thus allowing for early optimization of the treatment. Traditionally, the therapeutic efficacy of myopia control has been evaluated over an extended period (usually years of treatment), and clinicians may not realize that the prescribed treatment dose is ineffective until after a long time. This is important because myopia progression is usually rapid in the early stages, and early optimization of treatment can promote maximum therapeutic efficacy for myopia control. In addition, myopia progression is usually unidirectional, and the associated eye growth cannot be reversed, so a determination of poor efficacy after 1 to 2 years represents a loss of 1 to 2 years of treatment effect that cannot be recovered. If monitoring of myopia progression over a period of 6 months or longer shows that the patient is still progressing rapidly, a reasonable decision can be made to increase the treatment dose to a range where side effects are expected and manage those side effects with photochromic, varifocal glasses, or consider other forms of treatment, even though the level of receptor blockade is apparently sufficient to minimize side effects.

[0165] In the absence of a personal baseline assessment, treatment can also be adjusted by using normative data for various parameters as Figure 5 described.

[0166] During long-term treatment, which can often last for several years, regular measurements will help determine whether receptor upregulation is potentially reducing the effectiveness of the formulation. When treatment is terminated after a long period of time when receptor upregulation may have occurred, there may be increased reactivity of pupil light and accommodation responses and weakened accommodation-aggregate responses. This presents a risk of rebound growth of the eye that the initial treatment was intended to slow. In this case, restarting treatment with gradually reduced concentrations or less than once a day dosing can re-establish normal levels of receptor function. The dosing concentration or frequency can then be slowly reduced over weeks or months to prevent this type of upregulation effect from reoccurring.

[0167] The above method is based on the assumption that the estimated intraocular concentration and the dose applied to the cornea will be linearly related to the dose achieved in the eye, consistent with the observation that tear-to-aqueous humor drug transfer can be described by first-order kinetics. This assumption has also been shown to be reasonable experimentally for drugs that affect pupil size, such as pilocarpine and the antimuscarinic drug tropicamide (Yoshida S and Mishima S: A pharmacokinetic analysis of the pupil response to topical pilocarpine and tropicamide. Jpn J Ophthalmol 19:121, 1975). However, this assumption may vary from subject to subject and is affected by factors such as the amount of melanin in the iris that can provide non-receptor binding sites for antimuscarinic drugs.

[0168] In addition, machine learning based on data obtained from patients before and after initiation of treatment with topical antimuscarinic agents can help further refine the above algorithms. Anonymous data including basic patient demographic information (i.e., age, race, country, sex, and iris pigmentation pattern / degree), treatment history (concentration of active ingredient of eye drops and frequency of use), and measurements of the various oculomotor parameters described above over time can be collected at different testing sites and then transferred to a centralized or cloud-based computer system for further analysis to improve treatment methods.

[0169] This data can be used in a variety of ways:

[0170] 1) Improve the accuracy of normative pre-treatment data and allow better matching of a given patient to a matched comparable control;

[0171] 2) improving algorithms for adjusting doses or treatment regimens based on the estimated degree of beta-blockade to ensure that, if treatment adjustment is necessary, the modified treatment has a higher chance of achieving the desired level of beta-blockade with a single treatment change;

[0172] 3) Once the effects of treatment have been measured in many patients of different ages, backgrounds, and eye colors, analysis of the ultimate optimal treatment level for a given combination of demographic characteristics will provide recommendations for appropriate starting treatment parameters (e.g., in terms of drop concentration, drop size, and frequency).

[0173] Modulation of intraocular concentrations of antimuscarinic drugs

[0174] Under the guidance of the above-mentioned systems and methods of the present invention, the simplest way to achieve different intraocular concentrations is to change the concentration of the active ingredient in the eye drops. Since different drop concentrations will generally require regulatory approval, it is likely that only a small number of concentrations will be available. For atropine, the dosage range currently approved for ocular use is 1.0% and 0.5%. In addition, it is likely that other concentrations will be made available: 0.01%, 0.02%, 0.05% and 0.1%. Drugs such as atropine have a long duration of action due to their very high receptor affinity, with the effect lasting for 6-12 days. On this basis, atropine eye drops are usually only given once a day, but this may be more frequent than necessary. This also provides another way to change the intraocular concentration, namely changing the frequency of treatment.

[0175] Due to the persistence, treatment can be given less frequently than once daily, with a minimum of once a week for continued action (or lower for pulsed treatment regimens to prevent receptor upregulation), up to an approximate upper limit of four times a day, which is related to patient acceptance. Combining these two approaches provides a matrix of potential treatment strategies that provide more flexible and optimized treatment over a limited range of eye drop concentrations.

[0176] The total relative doses applied across these different options are shown below in Table 1, where 0.01% atropine once daily is a reference value of 1.0. If the initial treatment regimen does not provide an appropriate level of receptor blockade to achieve both possible myopia control efficacy and minimal side effects, a table such as the following table can be used together with estimates of receptor blockade based on measurements of pupillary responses, accommodation responses, and accommodation-convergence responses using the devices and methods of the present invention to determine an alternative treatment regimen.

[0177] Table 1

[0178] Concentration of eye drops

[0179]

[0180]

[0181] Using the systems and methods described above, the effects of low-dose atropine (0.01%) and another antimuscarinic drug, cyclopentolate at a reduced concentration (0.05%), were evaluated in human subjects, as outlined in the following examples.

[0182] Example 1: Pupillary responses before and after low-dose atropine - pupillometer

[0183] Figure 9 Shows the dynamic pupillary responses of a single subject before and one day after instillation of a diluted preparation of atropine at a concentration of 0.01%. The baseline difference in pupil size was only 0.6 mm and this depends on a range of factors including emotional state, light adaptation, and the activity of the slow ipRGC system. The maximum difference in the light response shows a much larger difference in the amount of pupil constriction obtained, with a peak difference of 1.6 mm at 1.8 seconds and then a slower return to baseline. In this case, the subject also showed a faster return to baseline when using atropine.

[0184] Figure 10 Shows the rate of change of pupil size, where the time point of 2x latency (approximately 400 milliseconds or 0.4 seconds) is shown as a dashed line. The ratio of the difference in rates (in this case 65%) between the post-treatment response and the pre-treatment response (V400 post and V400 pre ) at this time point indicates the degree of receptor blockade, which is much greater than can be imagined from the small difference in baseline pupil size shown in Figure 4 . Since the antimuscarinic drug is a receptor antagonist, the estimated level of receptor blockade is 1 - (V400 post / 400 pre ), i.e., 35%.

[0185] Example 2: Control system with an open-loop accommodative convergence system - accommodative convergence

[0186] Figure 11Shows the accommodation control system when the convergence system is open-loop by covering one eye. If the response of the ciliary body is weakened due to partial receptor blockade, the feedback nature of the accommodation response will enhance the response of the accommodation control center and result in sending a larger signal to the ciliary body than normal. This will partially compensate for the receptor blockade that causes a partial weakening of the accommodation response. Since there are no parallax cues in monocular viewing, this same enhanced internal signal is transmitted to the convergence center that is not receiving the control signal. This signal is then transmitted to the medial rectus extraocular muscle that is not affected by atropine or other antimuscarinic actions to produce accommodative convergence. Measuring the change in eye position for a given accommodative stimulus or response allows calculation of a value called the AC / A ratio. This varies among subjects, but according to control theory, low-dose antimuscarinic treatment results in an increased AC / A ratio. Therefore, measuring the AC / A ratio before and after treatment with a low-dose antimuscarinic agent provides a mechanism for estimating the extent of receptor blockade achieved and thus the potency and ocular penetration of the antimuscarinic ophthalmic drop formulation used.

[0187] The above-mentioned increased AC / A ratio was demonstrated as follows: Data were obtained from 12 normal subjects using serial dilutions of cyclopentolate from 0.25% to 0.05%, and the AC / A ratio (the ratio of accommodative convergence to accommodation) was measured using the gradient method at 6 meters and with negative lenses. At 33 cm, they maintained the ability to fully accommodate to read, but it was observed that the AC / A ratio increased by an average of 173% relative to the baseline. This increase was caused by the accommodation control system enhancing the signal it sends to the ciliary body with partial receptor blockade to achieve a comparable amount of accommodation. Therefore, this increase indicates a receptor blockade of 1 - 100 / 178 = 0.42 or 42%.

[0188] Consistent with the concept that low-dose formulations may be associated with response variability, reflecting ocular penetration due to low drug diffusion gradients and other issues, such as Figure 12 shown, a broad variation in the AC / A ratio change among subjects was observed. In this case, the AC / A ratio is defined in meter angles / diopters, and in these units, the standard AC / A is approximately 1.0.

[0189] Regarding receptor regulation, there is evidence that this does apply to muscarinic receptors. Animal studies of nerve agents that inhibit acetylcholinesterase leading to overstimulation of muscarinic receptors and subsequent prolonged downregulation. Studies of the nerve agent soman (pinacolyl methylphosphonofluoridate) in rats (Dabisch et al. 2007 TOXICOLOGICAL SCIENCES 100(1), 281-289) have shown that pupil size returns to baseline within 2 days of exposure to the agent, but other aspects of pupil function measured (including the light reflex, acetylcholinesterase activity, and pharmacological muscarinic receptor responsiveness) do not normalize for up to 10 days.

[0190] Figure 7 A schematic view of a clinical measurement device / apparatus 12 in the form of a pupillometer 12 suitable for use in the systems and methods of the present invention described above is shown, where the pupillometer 12 uses open-loop operation of the pupil light reflex. More specifically, the clinical measurement device / apparatus 12 for monitoring the intraocular penetration of an ophthalmic drug and / or the receptor response level in an eye 13 generally consists of a stimulation and test chamber 14, which is provided with an eye opening 15 for receiving the eye 13. The device 12 can be a monocular eye test device 12 having one chamber 14, or a binocular eye test device having two chambers 14 such that both eyes 13 are enclosed in separate chambers 14, and the distance between the axes of the two chambers 14 is adjusted to match the interpupillary distance.

[0191] The opening 15 of the chamber 14 is provided with a soft eye cup 16 to form a light seal around the eye 13 and to minimize ambient light from the environment. If a monocular device 12 is employed, the other eye should be covered.

[0192] Internally, the chamber 14 is provided with a white highly reflective coating 17 to form a miniature Ganzfeld chamber 18. The chamber 14 is further provided with a first infrared light source 19 in the form of an infrared (IR) emitting light-emitting diode (LED), a second short-wavelength visible light source (about 440 - 480 nm) 20 in the form of a short-wavelength visible light-emitting LED, and a third long-wavelength light source (about 550 - 640 nm) 21 in the form of a long-wavelength light-emitting LED.

[0193] The chamber 14 is further provided with a beam splitter 22, which can be a semi-silvered mirror, to ensure that the IR light irradiates the retina along the visual axis.

[0194] Externally, the device 12 is provided with an IR detector 23 in the form of an IR camera or a photoelectric unit / photodiode 23. An infrared filter (not shown) is arranged in front of the IR camera or the photoelectric unit / photodiode 23.

[0195] The device is controlled by a controller 24, which can be a computer, that controls and records stimulation control, data acquisition, storage, and analysis functions. Importantly, the device 12 has a stepping function 25 for activating the long-wavelength visible LED 21 for a duration that is less than or equal to the latency of the pupil response.

[0196] The device 12 is operated by placing the eye 13 against the eye opening 15 in the stimulation and test chamber 14 at the soft eye cup 16. The IR-emitting LED 19 emits invisible infrared light that is directed into the pupil and then imaged back to the IR camera or the optoelectronic unit / photodiode 23. The infrared filter in front of the camera excludes visible light emitted from the short-wavelength-emitting LED 20 and the long-wavelength-emitting LED 21.

[0197] The short-wavelength visible light-emitting LED 20 is permanently on during testing. This light inactivates the rod cells and short-wavelength-sensitive cone cells (s-cones) through light adaptation and provides a stable baseline stimulus for the ipRGCs. This minimizes the effects of variable prior light adaptation and eliminates three of the five light-related inputs to the pupil response (rod cells, SWS cones, and ipRGCs). The reflective coating 17 of the test chamber 14 ensures that the adaptation light from the short-wavelength visible light-emitting LED 20 reaches all retinal regions within the eye 13 to maximize the light adaptation of the rod cells.

[0198] The long-wavelength light-emitting LED 21 emits long-wavelength light (550 - 640 nm) to preferentially stimulate the long-wavelength and medium-wavelength-sensitive cone cells. During testing, the long-wavelength light-emitting LED 21 is activated by a pulse function to irradiate the eye 13 for a period equal to the latency of the pupil light (e.g., approximately 200 milliseconds) or up to twice the latency (400 milliseconds). The short latency is a key feature for isolating the feedback loop aspects of the pupil light reflex and other more complex temporal features. The reflective coating 17 of the test chamber 14 ensures that the adaptation light from this LED 21 reaches all retinal regions within the eye to maximize the response.

[0199] The beam splitter or half-silvered mirror 22 ensures that the IR light irradiates the retina along the visual axis and is co-aligned with the IR camera or the optoelectronic unit / photodiode detector 23 to ensure that the entire pupil area is irradiated to enhance video analysis or pupil size calculation based on the total amount of reflected IR light.

[0200] Although standard pupillometers aim to determine the overall response of the system both sensorially and motorically, the device 12 is configured to eliminate many variable sensory inputs, many non-sensory bias effects on pupil size, and many aspects of the overall control system and feedback loop in order to estimate the functional level at the neuromuscular interface of the iris sphincter that causes pupil constriction.

[0201] Figure 8 is a schematic representation of an alternative embodiment of the device 12 of the present invention, in which a Maxwell imaging system is employed. The same numerals indicate the same components. As shown, in the device 12, the adaptation and stimulation source at AP2 is imaged into the artificial pupil (AP1) through two lenses (L4 and L3). This light source is then projected into the pupil plane (AP0) of the eye through lenses L2 and L1. Assuming that the projection aperture is larger than the pupil size, the system will operate in an open-loop manner for light stimulation because pupil constriction will not change the amount of light entering the eye. To maximize the pupil size, in this configuration, the adaptation light source can be turned off shortly before activating the stimulation light source. In this configuration, the pulse length is not critical for measuring the open-loop function, and thus the pulse length can be increased if desired to obtain a more robust pupil response.

[0202] The device 12 is a monocular or binocular test device 12 for measuring pupil size and recording the changes in the pupil over time with a time resolution (sampling rate) of at least 20 Hz and preferably 50 - 100 Hz. The faster the sampling rate, the greater the resulting time resolution. During the test, at least 30 cd / m 2 of short-wavelength (about 440 - 480 nm) adaptation light 20 and long-wavelength (at least about 550 nm to at most 650 nm) test light 21 operate. As indicated above, these can be implemented in the form of light-emitting diodes 20, 21 with appropriate diffusers.

[0203] Short wavelength adaptation light 20 is used to minimize the influence of the rod cell, short wavelength sensitive cone cell (s-cone) and ipRGC (intrinsic photoreceptor retinal ganglion cell) that usually contribute to pupil reaction. Although it is the normal part of pupil reaction, in this device, the input of these cells is useless because ipRGC reaction is very slow and long-lasting, and rod cell contribution is very sensitive to previous light adaptation. The variable state that rod cell adapts to provides the important source of pupil light reaction variation. In the dark, need to reach 30 minutes to fully recover rod cell function, but need 2-10 minutes in short wavelength adaptation light, and rod cell can be effectively suppressed. Therefore preferably, suppress rod cell and measure the pupil light reaction that is derived from middle wavelength and long wavelength sensitive cone cell (m-cone and l-cone), to eliminate this source of sensation variability of pupil test. The reaction that m-cone and l-cone drive is also faster and more short-lived than the reaction that rod cell and ipRGC drive usually, and therefore can better measure the activity of receptor in pupil muscle fiber. The long-wavelength test light 21 preferentially stimulates the medium- and long-wavelength-sensitive cones and has minimal effect on any remaining functional rods or ipRGCs. This provides additional isolation of the m-cone and l-cone responses. The test protocol involves first activating the adapting light 20, followed by a short pulse of the long-wavelength test light 21 to stimulate the pupillary light response.

[0204] As discussed above, the feedback nature of the pupillary light reflex complicates the assessment of the degree of receptor blockade. To assess the pupillary light response without influencing the results through the feedback loop, the simplest approach is to make the duration of the pulse of long-wavelength test light 21 the same as the latency of the pupillary light response (approximately 170-220 milliseconds). In this way, the stimulus can be removed before the pupil begins to respond. The device 12 thus operates in an open-loop manner, completely unaffected by the feedback loop. At a time period of two times the latency (2LP, corresponding to 340-440 milliseconds), the eye's pupil control system effectively ceases to respond to the stimulus, and this is the optimal time to determine pupillary response parameters in order to estimate the degree of receptor blockade. At this 2LP time point, the change in pupil size from baseline, the speed of pupil constriction at this time, and the integral of the pupil size change during the interval between stimulus onset + latency and stimulus onset + 2x latency can be used to characterize the response. Peak constriction will typically occur later than this time point, but since the system is operating in an open-loop manner, this parameter can also be used.

[0205] If longer pulses such as 1 second pulses are used to ensure large pupil responses, the system responds in an open loop manner for a period equal to twice the latency of the pupillary light reflex, i.e., 340 - 440 milliseconds. The pupil will start to constrict at 170 - 220 milliseconds, but as part of the feedback loop, the effect of this constriction is not apparent until another latency has expired, so the threshold is 2X latency (2LP). At this 2LP time point, the change in pupil size from baseline, the speed of pupil constriction at this time, and the integral of the pupil size change during the time interval of stimulus onset + latency time and stimulus onset + 2x latency time represent the open loop component of the pupil response.

[0206] An alternative approach is to use Figure 8 the more complex Maxwell viewing optical system shown to deliver light to the eye 13 by imaging onto a fixed artificial pupil (which is smaller than the patient's natural pupil) in the pupil plane. In this case, the pupil response will not be affected by the feedback loop because pupil constriction does not reduce the amount of light entering the pupil, provided the pupil remains larger than the projected pupil.

[0207] The device 12 or the device - computer combination calculates the necessary parameters of the pupil response from a sequence of measurements of pupil size over time. For this purpose, the pupil response can be measured monocularly or binocularly. An estimate of the degree of blockade of the muscarinic receptors in the anterior part of the eye is obtained by comparing one or more of the above - mentioned parameters (i.e., the speed at the 2LP time point, the change in diameter at 2LP, and the integral of the pupil size change from time (t) = latency to t = 2x latency) during treatment of the patient with the pre - treatment response of the same patient, or with a normative database, or with a reference. The ratio of the parameter during treatment, expressed, for example, as a percentage, to the baseline provides the simplest measure. Taking into account some measurement variability, the average of the ratios of several parameters will provide higher reliability, as will the average of repeated measurements.

[0208] Another feature of device 12 is the addition of components for measuring the eye accommodation response to changes in stimulus vergence. For the measurement of accommodation, the same principles apply, but the accommodation system has a slower initial response latency of 300 to 400 ms. For applications in estimating muscarinic blockade, presenting small step changes (1 - 2 diopters) in stimulus vergence is preferable to large changes in stimulus vergence. Within the device, the stimulus to accommodation is ideally provided by a fixation target that has sufficient spatial detail to provide a good focusing target. The target can be imaged using a Badal lens system, allowing the fixation target to be rapidly moved by a stepper motor to effect the stimulus change. Accommodation parameters comparable to those used to determine the effect of an anti - muscarinic agent on the pupil response are of interest: in particular, the change in accommodation speed at twice the latency (600 - 800 milliseconds), the amplitude of the change, and the integral of the accommodation change during the time (t) = latency to t = 2x latency. For this purpose, the accommodation response can be measured monocularly or binocularly.

[0209] The Badal stepper - motor system for stimulating the accommodation system can also be used for monocular viewing to stimulate the accommodation - convergence response, where accommodation - convergence is measured by the convergence movement of the non - viewing eye while the viewing eye remains fixed on the fixation target. Eye position can be measured in a variety of ways, including limbus tracking, video analysis, or the corneal reflection position relative to the pupil or limbus. The accommodation - convergence response can be defined in terms of prism diopters / change in accommodation stimulus (via the Badal lens stimulation system) or per diopter of accommodation.

[0210] Thus, the test sequence performed by device 12 can be summarized as follows:

[0211] 1) Occlude the other eye in the monocular test device;

[0212] 2) Position the observer's eye appropriately in the device;

[0213] 3) Activate the long - wavelength adaptation LED 21 for at least 2 minutes;

[0214] 4) Collect consecutive samples of the video at a high sampling rate (>25 Hz) starting at least 1 second before the light stimulus or the amount of IR light from the pupil reflection to obtain a baseline;

[0215] 5) Activate the stimulus short - wavelength LED 20 in pulses of 200 milliseconds or longer; and

[0216] 6) Extract the pupil diameter at each time point from the video or photoelectric sensor.

[0217] Then the data from the device can be subjected to the processing steps previously outlined in Figures 4 to 6 as follows:

[0218] 7) Smoothing the data with a filter to estimate the first derivative of the data extracted in step 6, i.e., the pupil size change rate;

[0219] 8) Calculate at least one of the following: maximum change in pupil diameter from baseline, change at 2x latency (approximately 400 milliseconds), pupil velocity at 2x latency (approximately 400 milliseconds), average velocity from a time point (i.e., latency) up to 2x latency, and peak velocity up to and including the 2x latency time point. Calculate the numerical integral of the change in pupil size from baseline to the 2x latency time point.

[0220] 9) Calculate the ratio of the observed parameter to the patient's pre-treatment baseline value, normative age-matched data, or reference group data to estimate the level of functional blockade of muscarinic receptors in the iris.

[0221] 10) The intraocular concentration of the drug at the receptor is determined based on the level of functional blockade of the muscarinic receptor and the receptor binding properties of the drug.

[0222] 11) Determine whether the current treatment produces therapeutic intraocular concentrations of the drug.

[0223] 12) If no, calculate the dosage adjustment needed to bring the intraocular concentration of the drug into the therapeutic range.

[0224] The device 12 may include a microprocessor unit to store and provide numerical analysis of the pupil light obtained, or be connected to a general purpose computer for this purpose. The device 12 may also be incorporated as a subcomponent into a comprehensive ophthalmometric device, such as those that measure axial length, corneal curvature, and refraction, to provide a single device suitable for managing all aspects of clinical myopia control.

[0225] As indicated above, Figure 7 and Figure 8 The device 12 is merely an exemplary device, and it should be noted that the test device 12 employed in the methods and systems of the present invention may be any clinical measurement device capable of measuring pupillary light response and / or accommodation and / or accommodation-aggregate and adapted to minimize sensory factors and feedback control system features that may affect these responses. The use of such devices in the systems and methods of the present invention is described above.

[0226] A more refined way of controlling the treatment regimen can be adopted to optimize treatment. Other parameters include the size of the eye drops. Due to the limited size of the tear film and the capacity of the inferior fornix of the eye to hold eye drops (6 - 8 microliters), the drop size is not a very effective way to change the absorption in the eye. Standard drops contain approximately 25 - 50 microliters of solution, and the excess amount beyond what the inferior fornix can hold drains out through the nasolacrimal duct or falls out of the eye. For standard-sized eye drops, viscosity has a significant effect on intraocular absorption by increasing the contact time of the drops with the eye. Therefore, fixed-concentration eye drops with different viscosities can also be used to achieve different intraocular concentrations.

[0227] Alternative methods of controlling concentration include dynamically mixing the active ingredient and a placebo preparation that is identical in other respects but does not contain the active ingredient, as is commonly done in clinical trials. Combining a 0.1% atropine preparation with a placebo can provide a wide range of clinically relevant concentrations using two preparations for which clinical trial data will be available.

[0228] Typically, the placebo will not be sold as a product, but in this case, the placebo is used as a diluent, and safety and tolerance studies similar to those of the active compound will already have been conducted in regulatory trials. The mixing of the two preparations can be achieved at the dispensing level, i.e., by mixing two approved preparations, the active drug and the placebo, in the required ratio to provide a vial with the required concentration, or within a dispensing device that contains two reservoirs, one for the active ingredient and one for the placebo, and releases a mixture of the two preparations. The ratio of the two can be defined by physical parameters such as a delivery nozzle fed by tubes of different diameters. A standardized dual-reservoir eye drop bottle can also be equipped with a range of different delivery nozzles that contain two delivery tubes of the same or different diameters. For example, this device can provide a flow-controlled dilution from two reservoirs, a 1:1 dilution for 0.05%, or a 1:3 (drug:placebo) dilution for 0.025%, or a 1:5 dilution for 0.017%.

[0229] Alternative methods for mixing may involve using an electric device such as a drop-on-demand delivery system as currently used in inkjet printers. There are two mechanisms, a thermal drop-on-demand system that would be suitable for temperature-stable drug / placebo preparations, and a piezoelectric drop-on-demand system that would be suitable for temperature-sensitive preparations. Two parallel delivery systems would be required to deliver configurable amounts of the active ingredient and placebo diluent to the eye surface. This delivery device would be similar to a configurable insulin injection device that delivers a single preparation.

[0230] The drop-on-demand technique can provide a smaller and configurable volume (e.g., 8 microliters) than conventional eye drop delivery devices, but delivers a similar absorption of drug into the eye with a volume comparable to the existing tear film volume (6 - 8 microliters) and the same active drug concentration as much larger conventional eye drops, despite having less systemic absorption (Lanchulev, T., Weinreb, R., Tsai, J.C., Lin, S. and Pasquale, L.R. High-precision piezo-ejection ocular microdosing: Phase II study on local and systemic effects of topical phenylephrine [High-precision piezo-ejection ocular microdosing: Phase II study on local and systemic effects of topical phenylephrine]. Therapeutic Delivery [Therapeutic Delivery], 2018, 9(1), 17 - 27). Thus, to achieve different levels of drug activity in the eye, the microdose volume should be in the range of 1 to 8 microliters. This can provide customized therapy from a small range of approved ophthalmic drug concentrations.

[0231] Compared to the highly sensitive corneal surface, the conjunctival surface is relatively insensitive. Thus, this also provides a mechanism for highly controlled drug delivery via contact devices that can deliver drugs across the conjunctival surface by iontophoresis, whereby the drug or molecule is transported across the epithelial surface by electrophoresis and electroosmosis. The delivery concentration depends on the source concentration of the formulation, the surface area of the delivery system, the duration of application, and the electric potential. Several other prior arts can also be used to deliver ophthalmic drugs, and these techniques include microfluidic ion pumps.

[0232] In an alternative application of the devices and methods of the present invention, in addition to monitoring only the effects of low-dose antimuscarinics, a pharmacological challenge can also be performed and measured with the described devices to provide a more direct assessment of receptor blockade. The method can also be used to calibrate the relationship between the oculomotor parameters measured with the devices of the present invention and receptor blockade in a given clinical population.

[0233] For example, to assess the degree of pharmacological blockade, the response of the pupil or accommodation system to a topically applied muscarinic agonist at a concentration sufficient to achieve a maximal physiological response through high levels of receptor binding is measured. Such agents include pilocarpine and oxotremorine. These drugs will typically cause a strong pupillary constriction (miosis). This effect will be reduced proportionally to the amount of receptor blockade caused by a low-dose muscarinic antagonist such as low-dose atropine. The degree to which low-dose antimuscarinics attenuate the pupillary and accommodation responses to a muscarinic agonist measured using this device provides a direct estimate of receptor blockade.

[0234] The embodiments of the present invention described with reference to the accompanying drawings include computer devices and / or processes executed in computer devices. However, the present invention also extends to computer programs, in particular computer programs stored on or in a carrier adapted to put the present invention into practice. The program may be in the form of source code, object code, or a code intermediate source and object code, such as in a partially compiled form or any other form suitable for implementing the method according to the present invention. The carrier may include a storage medium such as a ROM, for example a memory stick or a hard disk. The carrier may be an electrical or optical signal that can be transmitted via an electrical or optical cable or by radio or other means.

[0235] In the specification, the terms "comprise," "comprises," "comprised," and "comprising," or any variations thereof, and the terms "include," "includes," "included," and "including," or any variations thereof, are considered to be fully interchangeable and should all be given the broadest possible interpretation, and vice versa.

Claims

1. A system for monitoring the intraocular concentration level of an anticholinergic ophthalmic drug in a patient, comprising: An accommodation or accommodative convergence measurement device for testing the accommodation or accommodative convergence response to the anticholinergic ophthalmic drug, the device being configured to test the patient to extract data regarding the accommodation or accommodative convergence response, and the system being configured to: Estimate the intraocular concentration of the anticholinergic ophthalmic drug based on the extracted data, wherein the intraocular concentration is estimated by calculating at least one data parameter value based on the extracted data and comparing it with a reference database of known data parameters, the at least one data parameter including the maximum change in pupil diameter from baseline, the size change at 2x latency, the pupil velocity at 2x latency, the average velocity up to 2x latency, the peak velocity up to and including the 2x latency point, and the area under the curve at 2LP, accommodation or accommodative convergence parameters.

2. The system of claim 1, wherein: Calculate an accommodation or accommodative convergence parameter value from the open-loop phase of the accommodation or accommodative convergence response.

3. The system according to claim 1, wherein Estimate the level of receptor blockade caused by the anticholinergic ophthalmic drug by comparing the accommodation or accommodative convergence parameter value with a reference database including the patient's baseline before treatment.

4. The system according to claim 1, wherein, Estimate the level of receptor blockade caused by the anticholinergic ophthalmic drug by comparing the accommodation or accommodative convergence parameter value with a reference database including a normative database or reference group data.

5. A system as claimed in claim 3 or claim 4, wherein: Calculate the intraocular concentration level of the anticholinergic ophthalmic drug based on the estimated level of receptor blockade.

6. The system according to claim 5, further comprising: Determine the optimal treatment regimen based on the intraocular concentration of the anticholinergic ophthalmic drug.

7. The system of claim 6, comprising: Evaluate whether the calculated intraocular concentration is within the therapeutic range.

8. The system according to claim 7, comprising: Determine the ratio of the calculated intraocular concentration to the desired intraocular concentration and calculate the dose or dosing frequency accordingly.

9. The system according to claim 8, further comprising: Adjust the dose as needed.

10. The system of claim 9, wherein: The anticholinergic ophthalmic drug is selected from the group consisting of atropine, homatropine, cyclopentolate, tropicamide, hyoscyamine, and scopolamine.

11. The system according to any one of claims 6 to 10, wherein: The treatment regimen is a myopia treatment regimen.

12. The system of claim 1, wherein: The accommodation or accommodative convergence measurement device includes a pupillometer.

13. The system according to claim 12, wherein, The pupillometer includes: A stimulation / test chamber; A short-wavelength visible light source; and A long-wavelength light source, wherein the long-wavelength light source is configured to be activatable for a duration less than or equal to the latency of the eye pupil response.

14. The system of claim 13, wherein: The pupillometer includes a step or pulse function for activating the long-wavelength light source for a duration less than or equal to the latency of the eye pupil response.

15. A system as claimed in claim 13 or claim 14, wherein: The short-wavelength visible light source is configured to be permanently on during monitoring.

16. The system according to claim 13, wherein, The device for testing includes an accommodation or accommodative convergence measurement device.

17. The system according to claim 1, wherein, The accommodation or accommodative convergence measurement device includes a controller for controlling and recording stimulation control, data acquisition, storage, and analysis functions.

18. The system according to claim 17, wherein, The controller includes a computer.

19. A method for monitoring the intraocular concentration level of an anticholinergic ophthalmic drug in a patient, comprising: Testing the patient with an accommodation or accommodative convergence measuring device to extract data regarding the accommodation or accommodative convergence response, and estimating the intraocular concentration of the antimuscarinic ophthalmic drug based on the extracted data by calculating at least one data parameter value and comparing it with a reference database of known data parameters, wherein the at least one data parameter includes the maximum change in pupil diameter from baseline, the size change at 2x latency, the pupil velocity at 2x latency, the average velocity up to 2x latency, the peak velocity up to and including the 2x latency point, and the area under the curve at 2LP, accommodation or accommodative convergence parameters.

20. The method according to claim 19, wherein, Calculating an accommodation or accommodative convergence parameter value from the open-loop phase of the accommodation or accommodative convergence response.

21. The method according to any one of claims 19 to 20, wherein Estimating the level of receptor blockade caused by the antimuscarinic ophthalmic drug by comparing the accommodation or accommodative convergence parameter value with a reference database including the pre-treatment patient baseline.

22. The method according to any one of claims 19 to 20, wherein Estimating the level of receptor blockade caused by the antimuscarinic ophthalmic drug by comparing the accommodation or accommodative convergence parameter value with a reference database including a normative database or reference group data.

23. The method according to claim 21, wherein Calculating the intraocular concentration level of the antimuscarinic ophthalmic drug based on the estimated level of receptor blockade.

24. The method according to claim 22, wherein, Calculating the intraocular concentration level of the antimuscarinic ophthalmic drug based on the estimated level of receptor blockade.

25. The method according to claim 19, wherein, The antimuscarinic drug is selected from the group consisting of: atropine, homatropine, cyclopentolate, tropicamide, hyoscyamine, and scopolamine.

26. The method according to any one of claims 19 to 20, further comprising: The step of smoothing the data with a filter.

27. The method according to any one of claims 19 to 20, further comprising: The step of performing machine learning based on the data obtained from the patient.

28. The method according to any one of claims 23 to 24, further comprising: The step of smoothing the data with a filter.

29. A method for determining the intraocular concentration of an antimuscarinic ophthalmic drug, comprising: Testing the patient with a test device to extract data regarding the pupil response or accommodation response, and Estimating the intraocular concentration of the antimuscarinic ophthalmic drug based on the extracted data to monitor the intraocular concentration level of the antimuscarinic ophthalmic drug in the patient, wherein the intraocular concentration is estimated by calculating at least one data parameter value and comparing it with a reference database of known data parameters, and the at least one data parameter includes the maximum change in pupil diameter from baseline, the size change at 2x latency, the pupil velocity at 2x latency, the average velocity up to 2x latency, the peak velocity up to and including the 2x latency point, and the area under the curve at 2LP, accommodation or accommodative convergence parameters.

30. The method according to claim 29, wherein, Calculating at least one data parameter from the open-loop phase of the pupil or accommodation response.

31. The method according to claim 29 or claim 30, wherein, Estimating the level of receptor blockade caused by the antimuscarinic ophthalmic drug by comparing the at least one data parameter with a reference database including the pre-treatment patient baseline.

32. The method according to claim 29 or claim 30, wherein, Estimating the level of receptor blockade caused by the antimuscarinic ophthalmic drug by comparing the at least one data parameter with a reference database including a normative database or reference group data.

33. The method according to claim 31, wherein, Calculating the intraocular concentration level of the antimuscarinic ophthalmic drug based on the estimated level of receptor blockade.

34. The method according to claim 32, wherein, The intraocular concentration level of the antimuscarinic ophthalmic drug is calculated based on the estimated receptor blockade level.

35. The method according to claim 29, wherein, The antimuscarinic drug is selected from the group consisting of atropine, homatropine, cyclopentolone, tropicamide, hyoscyamine and scopolamine.

36. The method according to any one of claims 29 to 30, further comprising: The step of smoothing the data using a filter.

37. The method according to any one of claims 33 to 34, further comprising: The step of smoothing the data using a filter.

38. The method according to any one of claims 29 to 30, further comprising: The step of performing machine learning based on the data obtained from the patient.

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