A kit of parts,medicament and method

Abstract

A kit of parts including a medical apparatus for emitting electromagnetic radiation having a wavelength of 475 nm to 510 nm towards one or both eyes of a subject and a pharmaceutical composition for r

Description

The present invention relates to a kit of parts, a medicament and a method. In particular, but not exclusively, the present invention relates to a kit of parts comprising a medical apparatus for emitting electromagnetic radiation towards one or both eyes of a subject and a pharmaceutical composition for reducing blood glucose concentration in the subject. The present invention also relates to a medicament for use in treating hyperglycaemia, and a method of reducing, or prevention of, hypoxia-inducible factor 1 (HIF-1) expression in one or both eyes of a subject BACKGROUND Phototherapy has been used for various therapeutic and cosmetic purposes. It generally involves the use of specific wavelengths of light radiation being administered to a patient. Phototherapy may be used to treat chronic infections such as hepatitis (A, B or C), bacterial infections, wounds, precancer conditions, seasonal affective disorder (SAD), various dermatological and cosmetic purposes such as skin rejuvenation, and various eye diseases such as diabetic macular edema, retinopathy of prematurity, wet or dry age-related macular degeneration (AMD) and diabetic retinopathy, for example. Diabetic retinopathy is a condition in which damage to the retina in the eye occurs and is caused by diabetes. More specifically, diabetic retinopathy is the result of microvascular retinal changes where hyperglycaemia-induced intramural pericyte death and thickening of the basement membrane cause damage to the wall of blood vessels in the eye. This damage changes the formation of the blood-retinal barrier and also makes the retinal blood vessels become more permeable. Furthermore, small blood vessels, such as those in the eye, are particularly vulnerable to poor blood sugar control. An overaccumulation of glucose and / or fructose damages the small blood vessels in the retina. Damaged blood vessels are likely to leak fluid and lipids onto the macula, and therefore lead to impaired vision and, ultimately, blindness. It is also recognised that a hypoxic environment within the retina contributes to the production of new blood vessels, which are often weak or damaged as noted above, and hence contribute to the progression of retinopathy. In particular, low light levels - such as during sleeping - increases oxygen demand within the eye (known as “dark adapting”), thereby resulting in the starvation of oxygen in the retina and hence a hypoxic environment. This hypoxia results in a pathway (see FIG. 1 as discussed below), which ultimately results in the accumulation of hypoxia inducible factor 1 (HIF-1) in the nucleus of cells. This then causes a cascade of reactions which result in the increase in production and over expression of vascular endothelial growth factor (VEGF). VEGF is part of a system that restores oxygen supply to tissues when the blood circulation is inadequate by stimulating vasculogenesis (new vessel formation) and angiogenesis (proliferation and migration of vessel cells). As such, new blood vessels are formed within the eye, but those new blood vessels are often weak and damaged as described above. Recently, Guo et al. (Cell Reports (2023) 42(1)) and Babapoor-Farrokhran etal. (Proceedings of the National Academy of Sciences (2023) 120(50)) have shown that accumulations of VEGF, resulting from increased HIF-1 expression, is detrimental to retinal health. FIG. 1 illustrates the chain of reactions that leads to increased VEGF production, increased angiogenesis and ultimately the progression of diabetic retinopathy. A hypoxic environment (step 101), which is caused by dark adaptation of the cells in the retina during sleep, causes HIF-1 to accumulate in the nucleus of cells within the retina (step 104) as discussed above and recognised by Babapoor-Farrokhran et al. Likewise, a drop in blood glucose levels (step 102), for example from a high blood glucose level (hyperglycaemia) to a normal blood glucose level or from a normal blood glucose level to a low blood glucose level (hypoglycaemia), also causes HIF-1 to accumulate in the nucleus (step 104), as recognised by Guo et al. The accumulation of HIF-1 in the nucleus (step 104) initiates the production of VEGF mRNA into the cytoplasm (step 106). The increased VEGF mRNA (step 106) produces VEGF causing increased levels of VEGF expression (step 108) which, in turn, increases vasculogenesis and angiogenesis in the retina (step 110). As discussed above, the formation and growth of new, although weak and / or already damaged, blood vessels causes damage to the retina. Non-symptomatic episodes of hypoglycaemia can also result in the accumulation of HIF-1. For example, a drop in blood glucose levels in a subject with chronic hyperglycaemia to normal levels can result in this increase in HIF-1 accumulation. These states are common in both type-1 and type-2 diabetics and can occur in a variety of situations, such as overnight, when food is not being consumed, or when undergoing treatment to control their blood glucose levels. Examples of treatments to control a blood glucose level of a subject may include the introduction of closed-loop glucose control (such as artificial pancreas systems), glucose control medications or calorie restricted diets. Thus, it can be seen that the response to hypoglycaemia is more extreme in a hypoxic environment in the retina. That is, there is a greater accumulation of HIF-1 when cells in the retina are hypoxic than would be expected from the sum of the accumulation of HIF-1 from hypoxia and from hypoglycaemia. This is due to the two pathways acting synergistically to increase HIF-1 accumulation: one from the hypoxic environment (as the retina consumes more oxygen in low light levels, thus increasing HIF-1 accumulation) and another from the hypoglycaemic environment (as the lowering of glucose causes HIF-1 accumulation). As HIF-1 accumulates and results in vasculogenesis and angiogenesis, the new blood vessels likewise require a further oxygen and glucose uptake, thereby resulting in yet further hypoxia and hypoglycaemia in the retina, which stimulates yet further HIF-1 accumulation. As can be seen, this results in a cycle in which the retina continually produces weak and / or damaged blood vessels, and hence the eye can become rapidly damaged. Accordingly, diabetics who attempt to control glucose levels to bring their glucose levels into the correct range would have an accumulation of HIF-1 in the retina and an acceleration of the development of symptoms of diabetic retinopathy. Indeed, drugs that reduce blood glucose levels, such as glucagon-like peptide 1 (GLP-1) agonists, will have the same fundamental effect as other pathways that result in drops in blood glucose, due to the impact on the HI F-1 pathway resulting from the lowering of blood glucose levels. For this reason, the use of GLP-1 agonists, and other blood glucose lowering drugs, have been contraindicated for those suffering from, or at risk of, diabetic retinopathy. Generally, diabetic retinopathy can be treated by preventing the complete dark adaptation of the eye by providing some degree of light radiation to the eyes or eyelids during sleep. This is because, during dark adaptation, the eye requires an increased oxygen level, and thus the blood vessels must work harder during dark adaptation. Therefore, by preventing complete dark adaptation of the eye, the blood vessels are less stressed and the cells of the retina can rejuvenate overtime. Thus, HIF-1 accumulation is reduced and ultimately VEGF expression is reduced. It has been found useful to administer the radiation to the eye area by providing a mask type of device for a patient to wear during sleep, the mask configured to be secured over the patient’s head to cover the eye area, and adapted to include electromagnetic radiation emitting sources in the region of the eyes. The radiation acts to stimulate the rods of the eye leading to hyperpolarization and desensitization of the rod cells, which lowers their metabolic rates and hence results in a drop in oxygen consumption in the retina. WO2011 / 135362, WO2012 / 025398, WO2012 / 025399, WO2013 / 124615, WO2014 / 118571 and WO2015 / 033114 disclose various radiation treatment apparatuses for directing electromagnetic radiation towards a patient. Therefore, there is a need to prevent, or at least slow, the onset and development of diabetic retinopathy whilst allowing a subject with hyperglycaemia to reduce their blood glucose levels. Particularly, there is a need for a subject to be able to concurrently treat and / or control diabetes and diabetic retinopathy. The present invention seeks to solve such problems. SUMMARY According to a first aspect of the invention, there is provided a kit of parts comprising: a medical apparatus comprising a radiation source for emitting electromagnetic radiation towards one or both eyes of a subject, wherein the medical apparatus is configured to emit electromagnetic radiation at a wavelength from 475 nm to 510 nm; and a pharmaceutical composition comprising an effective amount of medicament for use in reducing a blood glucose concentration of the subject. Advantageously, the kit of parts is for use by a subject with hyperglycaemia who is at risk of, or is suffering from, diabetic retinopathy. The subject can be treated with the pharmaceutical composition, and following administration of the pharmaceutical composition, the subject can use the medical apparatus for a period of time, such as during sleep. The medical apparatus is capable of emitting electromagnetic radiation towards one or both eyes of the subject for a period of time, such as during sleep. This combination of the pharmaceutical composition and the medical apparatus will reduce, or mitigate, the excessive accumulation of HIF-1 and, ultimately, undesirable excessive VEGF expression in the retina when the cells in the retina are hypoxic in a dark environment (such as during sleep), thereby slowing the onset and development of diabetic retinopathy. In this way, pharmaceutical compositions for reducing blood glucose concentration, which are usually contraindicated for those suffering from retinopathy, may be prescribed to retinopathic subjects, particularly concurrently with the appropriate electromagnetic radiation administration as discussed herein. According to a second aspect of the invention, there is provided a package comprising the kit of parts. According to a third aspect of the invention, there is provided a medicament for use in the treatment of hyperglycaemia in a subject, wherein the medicament is administered to the subject and wherein electromagnetic radiation having a wavelength from 475 nm to 510 nm to one or both eyes of the subject is subsequently administered. According to a fourth aspect of the invention, there is provided medicament for use in the treatment of hyperglycaemia in a subject receiving concurrent treatment for retinopathy, wherein the concurrent treatment for retinopathy comprises the administration of electromagnetic radiation to one or both eyes, wherein the electromagnetic radiation has a wavelength from 475 to 510 nm. Concurrent treatment for retinopathy is treatment that occurs whilst the medicament is acting within the body, for example, during the elimination half-life of the medicament. Accordingly, the administration of electromagnetic radiation to one or both eyes occurs following administration of the medicament and during the period of the elimination half-life of the medicament is a concurrent treatment. According to a fifth aspect of the invention, there is provided a method of reducing hypoxia induced factor (HIF-1) expression in one or both eyes of a subject, the method comprising administering a pharmaceutical composition comprising an effective amount of medicament for reducing blood glucose concentration of the subject, and subsequently administering electromagnetic radiation to one or both eyes of the subject, the electromagnetic radiation having a wavelength from 475 nm to 510 nm. Advantageously, the subject is treated with the pharmaceutical composition, or medicament, and following administration of the pharmaceutical composition or medicament, the subject will use the medical apparatus. The medical apparatus is capable of emitting electromagnetic radiation towards one or both eyes of the subject. This combination of the pharmaceutical composition and the medical apparatus will reduce, or at least mitigate, the excessive accumulation of HIF-1 and ultimately excessive VEGF expression in the retina when cells in the retina are hypoxic during sleep, thereby slowing the onset and development of diabetic retinopathy. According to a sixth aspect of the invention, there is provided a method for the prevention of excessive HIF-1 expression in one or both eyes arising in the treatment of a subject with hyperglycaemia, the method comprising: administering a pharmaceutical composition comprising an effective amount of medicament for reducing blood glucose concentration in the subject and thereby increasing HIF-1 expression in one or both eyes of the subject by a predetermined amount; and administering electromagnetic radiation to one or both eyes of the subject, the electromagnetic radiation having a wavelength from 475 nm to 510 nm, in an amount effective to reduce HIF-1 expression by the predetermined amount. Advantageously, the subject is treated with the pharmaceutical composition. The treatment with the pharmaceutical composition reduces the blood glucose concentration in the subject and causes HIF-1 to accumulate in the retina. Following administration of the pharmaceutical composition, the subject will use the medical apparatus. The administration of electromagnetic radiation to one or both eyes of the subject will inhibit the accumulation of HIF-1 in the retina when cells in the retina are hypoxic in a dark environment (such as during sleep). Thus, the administration of electromagnetic radiation following administration of the pharmaceutical composition will prevent the excessive accumulation of HIF-1 in the retina that is caused by the reduction of blood glucose levels in the subject. Accordingly, diabetic retinopathy may continue to develop at a normal rate in the subject, as the administration of the pharmaceutical composition does not increase HIF-1 accumulation beyond the normal tolerable accumulation during periods in which cells of the retina are hypoxic in a dark environment (such as during sleep). According to a seventh aspect of the invention, there is provided a kit of parts comprising: a medical apparatus comprising a radiation source for emitting electromagnetic radiation towards one or both eyes of a subject, wherein the medical apparatus is configured to emit electromagnetic radiation at a wavelength from 475 nm to 510 nm; and a blood glucose monitor for measuring the blood glucose level of the subject. According to an eighth aspect of the invention, there is provided a method of treating, preventing, or ameliorating diabetic retinopathy or one or more symptoms of or conditions related to diabetic retinopathy, comprising: administering a medicament to a patient, wherein the medicament reduces a blood glucose concentration of the patient; and irradiating one or both eyes of the patient with electromagnetic radiation at a wavelength of 475 nm to 510 nm, wherein the patient is a patient diagnosed with or exhibiting symptoms of or a condition related to diabetic retinopathy. Advantageously, the kit of parts is for use by a subject with hyperglycaemia who is at risk of, or is suffering from, diabetic retinopathy. The subject can control their blood glucose levels with lifestyle changes, such as changes to their diet to a calorie-restricted diet, and monitor their blood glucose levels with the blood glucose monitor and following the initiation of the lifestyle changes, the subject can use the medical apparatus for a period of time, such as during sleep. The medical apparatus is capable of emitting electromagnetic radiation towards one or both eyes of the subject for a period of time, such as during sleep. This combination of the lifestyle changes and the medical apparatus will reduce, or mitigate, the excessive accumulation of HIF-1 and, ultimately, undesirable excessive VEGF expression in the retina when the cells in the retina are hypoxic in a dark environment (such as during sleep), thereby slowing the onset and development of diabetic retinopathy. In this way, the subject can make changes to the lifestyle, such as changes to their diet, to reduce their blood glucose levels, which is usually not recommended for those suffering from retinopathy, and such changes can be recommended to the subject, particularly concurrently with the appropriate electromagnetic radiation administration as discussed herein. In examples, the medical apparatus may be configured to emit electromagnetic radiation at a wavelength from 495 nm to 505 nm. In examples, the radiation source may comprise an electroluminescent emitter, a light emitting diode (LED), a light emitting cell (LEG), a light emitting electrochemical cell (LEEC) or an organic light emitting diode (OLED). In examples, the radiation source may comprise fluorescent or phosphorescent material. In examples, the medical apparatus may comprise a facial mask. In examples, the wavelength of the electromagnetic radiation may peak at 504 nm or 498 nm. In examples, the radiation source may be configured to emit electromagnetic radiation having a frequency of from 526 THz to 606 THz. In examples, the radiation source may be configured to emit electromagnetic radiation having a photon energy of from 2.17 eV to 2.50 eV. In examples, the radiation source may be configured to emit electromagnetic radiation at a wavelength from 475 nm to 510 nm. In some examples, the radiation source may be configured to emit electromagnetic radiation at a wavelength from 495 nm to 505 nm. In other examples, the medical apparatus comprises a filter for filtering the electromagnetic radiation emitted from the radiation source to a wavelength from 475 nm to 510 nm. In some examples, the filter may filter the electromagnetic radiation emitted from the radiation source to a wavelength from 495 nm to 505 nm. In yet other examples, the medical apparatus may comprise fluorophores configured to receive the electromagnetic radiation emitted from the radiation source and emit electromagnetic radiation at a wavelength from 475 nm to 510 nm. In some examples, the fluorophores may be configured to emit electromagnetic radiation at a wavelength from 495 nm to 505 nm. In examples, the medical apparatus may be configured to emit electromagnetic radiation at a brightness less than or equal to 100 cd / m2. In some examples, the medical apparatus may be configured to emit electromagnetic radiation at a brightness of 50 cd / m2 or 80 cd / m2. In examples, the medical apparatus may be configured to emit electromagnetic radiation having a ratio of scotopic luminous intensity to photopic luminous intensity of at least 1.85:1. In some examples, the ratio of scotopic luminous intensity to photopic luminous intensity may be at least 2:1. In some examples, the ratio of scotopic luminous intensity to photopic luminous intensity may be at least 3:1. In some examples, the ratio of scotopic luminous intensity to photopic luminous intensity may be at least 5:1. In examples, the pharmaceutical composition may be provided in the form of a tablet, a capsule, or a powder. In other examples, the pharmaceutical composition may be provided in the form of a pellet. The pellet may be a subcutaneous pellet. The pellet may be suitable for subcutaneous implantation. In yet other examples, the pharmaceutical composition may be provided in the form of a patch. The patch may be suitable for adhering the skin of the subject. In examples, the kit of parts may further comprise a vial or a container comprising the pharmaceutical composition. In other examples, the kit of parts may further comprise a pre-filled syringe comprising the pharmaceutical composition. In examples, the kit of parts may further comprise a dispensation device comprising the pharmaceutical composition. In one example, the dispensation device may be an infusion pump. In another example, the dispensation device may be a pre-filled syringe. In examples, the kit of parts may further comprise a closed-loop system comprising the pharmaceutical composition. In one example, the closed-loop system may be an artificial pancreas system. In some examples, the closed-loop system may comprise a dispensation device comprising the pharmaceutical composition. In some examples, the closed-loop system may also comprise a blood glucose monitor. In examples, the kit of parts may further comprise a blood glucose monitor. In some examples, the kit of parts may comprise a continuous blood glucose monitor. In other examples, the kit of parts may comprise a blood glucose meter. The kit of parts may further comprise a plurality of blood glucose testing strips and one or more lancets. In examples, the kit of parts may further comprise instructions to administer the pharmaceutical composition to the subject and subsequently use the medical apparatus to administer electromagnetic radiation to one or both eyes of the subject. In examples, the kit of parts may further comprise instructions for implementing a calorie-restricted diet to control their blood glucose levels. In examples, the kit of parts may further comprise a device comprising a controller and a user interface, wherein the device is configured to receive an input indicating administration of the pharmaceutical composition and subsequently to output one or more alerts to prompt the subject to use the medical apparatus. In some examples, the device may further include one or more of: a speaker, a screen, an antenna, and a motor for vibrating the device. The alarm may be an audial, visual and / or tactile alarm. In some examples, the alert may include one or more of: an alarm, a vibration, text displayed on a screen, or a flashing light. In some examples, the device may be a mobile phone. In other examples, the device may be a feature of the medical apparatus. In yet other examples, the device may be a stand-alone device. In some examples, the alert may be output at a time selected by the subject. In some examples, the alert may be output at the same time every day. In some examples, the input indicating administration of the pharmaceutical composition is received from the medical apparatus. In other examples, the input indicating administration of the pharmaceutical composition is input by a user, e.g. the subject, through the user interface of the device. In examples, the step of administering electromagnetic radiation to the one or both eyes of the subject may be subsequent to the step of administering the pharmaceutical composition. In examples, the electromagnetic radiation administered to the one or both eyes may have a wavelength from 495 to 505 nm. In examples, the electromagnetic radiation may be administered to one or both eyes of the subject during sleep. In examples, the electromagnetic radiation may be administered to one or both eyes of the subject for a period of time being from 0.5 to 12 hours, typically from 4 to 8 hours. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject during sleep each day for a period substantially equal to the elimination halflife of the medicament. In other examples, the electromagnetic radiation may be administered to one or both eyes of the subject for a period of time being from 0.5 to 12 hours, typically from 4 to 8 hours, for a treatment period substantially equal to the elimination half-life of the medicament. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject during sleep for a period of up to three months. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject during sleep for a period of one month. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject during sleep for a period of two months. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject during sleep for a period of three months. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject for a period of time being from 0.5 to 12 hours, typically from 4 to 8 hours, for a treatment period of up to three months. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject for a period of time being from 0.5 to 12 hours, typically from 4 to 8 hours, for a treatment period of one month. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject for a period of time being from 0.5 to 12 hours, typically from 4 to 8 hours, for a treatment period of three months. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject during sleep every time the subject sleeps. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject during sleep every night. In some examples, the electromagnetic radiation may be administered to one or both eyes of the subject during the entire sleep duration. In examples, the medicament may comprises one or more of a biguanide, a DPP-4 inhibitor, insulin, a gastric inhibitory polypeptide (GIP) analogue, a thiazolidinedione, a sulfonylurea, a SGLT-2 antagonist, a glucagon-like peptide 1 (GLP-1) agonist or a selective mineralocorticoid receptor antagonist. In some examples, the medicament may comprise any combination of a biguanide, a DPP-4 inhibitor, insulin, a GIP analogue, a thiazolidinedione, a sulfonylurea, a SGLT-2 antagonist, a GLP-1 agonist or a selective mineralocorticoid receptor antagonist. In examples, the medicament may comprise an incretin or an incretin mimetic. In some examples, the medicament may be a biguanide. The biguanide may be metformin. In such examples, the medicament may comprise one or more tablets or capsules comprising metformin, for example, 500mg of metformin. In some examples, the medicament may be a DPP-4 inhibitor. The DPP-4 inhibitor may be selected from the group comprising alogliptin, linagliptin, sitagliptin, saxagliptin, and vildagliptin. In such examples, the medicament may comprise one or more tablets or capsules comprising alogliptin, linagliptin, sitagliptin, saxagliptin or vildagliptin. In some examples, the medicament may be an incretin. In some examples, the medicament may be insulin. In some examples, the medicament may be a gastric inhibitory polypeptide (GIP) analogue, such as a GIP agonist. In some examples, the medicament may be a thiazolidinedione, or a glitazone. The thiazolidinedione may be used in combination with a biguanide (such as metformin), a sulfonylurea (such as glibenclamide, glicazide, glimepiride, glipizide or tolbutamide) or insulin. The thiazolidinedione may be pioglitazone (RS-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benyl)thiazolidine-2,4-dione). In some examples, the medicament may be a sulfonylurea. The sulfonylurea may be selected from the group comprising glibenclamide, glicazide, glimepiride, glipizide, and tolbutamide. In such examples, the medicament may comprise one or more tablets or capsules comprising glibenclamide, glicazide, glimepiride, glipizide or tolbutamide. In some examples, the medicament may be a SGLT-2 (sodium-glucose transport protein 2) antagonist. The SGLT-2 antagonist may be selected from the group comprising canagliflozin, dapagliflozin, empagliflozin and ertugliflozin. In such examples, the medicament may comprise one or more tablets or capsules comprising canagliflozin, dapagliflozin, empagliflozin or ertugliflozin. In some examples, the medicament may be a GLP-1 agonist. The GLP-1 agonist may be selected from the group comprising exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide and tirzepatide. In such examples, the medicament may comprise a vial, a container or a syringe comprising exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide or tirzepatide. In some examples, the medicament may be a selective mineralocorticoid receptor antagonist. The selective mineralocorticoid receptor antagonist may be finerenone. In such examples, the medicament may comprise one or more tablets or capsules comprising finerenone. The subject may be a patient. The subject may be a patient receiving treatment for hyperglycaemia. The subject may be a diabetic patient receiving concurrent treatment for hyperglycaemia. The subject may be a human subject or a human patient. In some examples, particularly in relation to the eighth aspect, the method is ordered such that it comprises the steps of administering a medicament to a patient, wherein the medicament reduces a blood glucose concentration of the patient; and then irradiating one or both eyes of the patient with electromagnetic radiation at a wavelength of 475 nm to 510 nm. In some examples, particularly in relation to the eighth aspect, the method results in a reduction of expression and / or accumulation of a hypoxia induced factor (HIF-1) in one or both eyes of the patient. In some examples, particularly in relation to the eighth aspect, the irradiating is carried out for about from 0.5 to 12 hours. In some examples, particularly in relation to the eighth aspect, the medicament comprises at least one of: biguanide, a DPP-4 inhibitor, a thiazolidinedione, an incretin, a GIP analogue, a thiazolidinedione, a sulfonylurea, a SGLT-2 antagonist, a GLP-1 agonist and a selective mineralocorticoid receptor antagonist. In some examples, particularly in relation to the eighth aspect, the irradiating is carried out for a time period equal to about an elimination half-life of the medicament. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which: FIG. 1 illustrates a chain of reactions that lead to increased HIF-1 expression and VEGF production, and thereby increased angiogenesis; FIG. 2 illustrates the scotopic and photopic luminosity functions; FIG. 3 illustrates a medical apparatus; and FIG. 4 illustrates a kit including the medical apparatus and a vial containing a pharmaceutical composition. In the drawings, like reference numerals refer to like parts. DETAILED DESCRIPTION Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The attention of the reader is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference. Rods and cones are the two main visual photoreceptor cells within the eye. Cones are primarily located around the centre of the field of vision, known as the yellow spot or the macula. The rods are mainly distributed around the areas of the retina outside of the macular. There are approximately 120 million rods in each eye and around 6 million cones. During dark conditions there is no light to stimulate rods and cones. In such dark conditions the rod cells maintain a polarized state and continually release neurotransmitters. Maintenance of this polarized state is an energy consuming process. The retina therefore requires an increased supply of oxygen and sugars during dark conditions. If a patient already has damaged blood vessels in the eye, the increased oxygen and sugar supply is not helpful in preventing further damage, or in the repair of, existing blood vessels. Upon absorption of light by a rod cell, a series of reactions shut the ion channels on the surface of the rod cell allowing the rod cell to become hyperpolarized and the release of neurotransmitters is suppressed. The oxygen and sugar demand from the retina is therefore lessened and the risk of damaged blood vessels is reduced. It is this suppression of neurotransmitters upon absorption of light and subsequent reduction in damage to blood vessels that has led to investigations into to use of light emitting masks for sufferers of diabetic retinopathy to help prevent further damage to blood vessels, and possibly allow damaged blood vessels to repair. FIG. 2 illustrates the general response of rods and cones to light across a spectrum of wavelengths. In other words, FIG. 2 illustrates the probability that a rod (curve 10) or cone (curve 12) will respond to the absorption of a photon of a particular wavelength by that cell. These curves are known in the art as the scotopic and photopic luminosity functions (curves 10 and 12 respectively). The rods are mainly responsive to light in the scotopic wavelength range (about 400 nm to 610 nm), and are most responsive to light at about 500 nm wavelength. Cones 12 (considered as a group including all three types of cones) are mainly responsive to light in the photopic wavelength range (about 475 nm to 650 nm), and are most responsive to light with a wavelength of about 575 nm. The inventors have realised that the response of both the rods and the cones to a specific wavelength of light should be considered when devising a light emitting apparatus. The rods and cones have different probabilities of responding to incident light, and that response, if any, is different between rods and cones. For example, a rod is much more likely than a cone to respond to photon of 450 nm wavelength. A photon at 550 nm wavelength, however, is more likely to stimulate a cone than a rod. The wavelength of light emitted by the medical apparatus is from 475 nm to 510 nm. In one example, the wavelength of light may be from 495 to 505 nm. These wavelengths allow for the selective activation of rods. For radiation treatment of the eye, a light source can be directed towards the eye of a subject or patient. FIG. 3 illustrates an example of a medical apparatus, which is a facial mask 20 suitable for securing one or more light emitting source 30, 32 in position in use. The light emitting source may be an OLED array, for example. The facial mask 20 includes supporting regions 22, 24 to be located adjacent to the eyes of a patient, the supporting regions 22, 24 each supporting a respective light emitting source. Of course, if only one eye is to be treated only one light source is required. The supporting regions 22, 24 are positioned to match the spacing between a patient’s eyes. This spacing may be the average spacing between eyes, or ‘tailor made’ to fit the requirements of the particular patient, or the supports may be adjustable regions that are moveable between predetermined limits. A securing strap 26, secures the apparatus to the patient’s head. The light sources are powered by at least one battery housed in or secured to the body 28 or the strap 26 of the mask. It will be appreciated that alternatively an external battery or power supply may also be used. Various facial masks for emitting light radiation towards the eyes are known per se. These types of facial mask are provided with a radiation source for emitting electromagnetic radiation to the eye. To customise the light received by the eye, the radiation source itself can be devised accordingly, or a filter or other means may be used to modify the electromagnetic radiation prior to reaching the eye. Although a medical apparatus including a facial mask has been described above, it will be appreciated that other types of apparatus may be used to secure a light source in position, for example goggles, visors or glasses. Alternatively, the medical apparatus may include a stand or handle with a radiation source for emitting electromagnetic radiation towards one or both eyes of a patient disposed on it, to form a lamp or torch or similar object, to conveniently and comfortably direct light towards the patient. Optionally the medical apparatus may contain a controller or other control mechanism, to control the dosage of radiation administered to the patient. The apparatus may include features such as a timer and / or sensors that detect when the patient is present or wearing the device. The dose may be administered such that the patient receives radiation for the entire sleeping period, or a period of, for example, from 0.5 hours to 12 hours, such as from 4 to 8 hours, within their overall sleeping period. Alternatively or in addition, the medical apparatus may have a user interface for enabling a patient or caregiver the capability to define the dosage period and / or dosage level, etc. Alternatively or in addition, the medical apparatus may include a connectivity feature, such as Wi-Fi or Bluetooth, to allow for the apparatus to be controlled by an external device such as an external controller, a computer or a mobile phone. The medical apparatus as described above is provided in combination with a pharmaceutical composition having an effective amount of medicament for reducing a blood glucose concentration of a subject or patient. FIG. 4 illustrates a kit 50 including the facial mask 20 and a vial 54 containing a pharmaceutical composition. The pharmaceutical composition contains a medicament that is effective at reducing a blood glucose concentration of the subject. The vial 54 may contain a single dose of the pharmaceutical composition. Alternatively, the vial 54 may contain multiple doses of the pharmaceutical composition. In this specific example, the vial 54 contains semaglutide (a GLP-1 agonist) in a liquid form for subcutaneous injection. The pharmaceutical composition may alternatively be provided in a pre-filled syringe or in a container. In other examples, the pharmaceutical composition may be provided in the form of a tablet, a capsule, a powder, a subcutaneous pellet, or a patch. The facial mask 20 and vial 54 are provided in a package 52. The package 52 may be a box, a case, a bag, or any other suitable means for holding the facial mask 20 and the vial 54. This allows the subject to receive the components required for treatment of the hyperglycaemia and diabetic retinopathy in a single package. The kit 50 can also contain a device (not shown) that can receive an input that indicates the pharmaceutical composition has been administered to the subject. The device includes a controller and a user interface. The user interface may include buttons or a touch screen. The device will alert the subject in order to remind the subject to use the facial mask 20 during sleep. The alert may be set by the subject to occur at the same time every day. The device may also alert the subject when a further dose of the pharmaceutical composition is required. The device may also include a display, a speaker, a light and / or a motor to vibrate the device. The alert could be a vibration, an audible alarm, text displayed on a screen, or a light. Alternatively, a device is not provided with the kit, instead, the subject can use an application on their mobile phone or other suitable device which provides the same function. The device may also include an antenna to receive data from the facial mask 20. The data may include the period of time the facial mask 20 was worn. The data may also include the battery level of the facial mask 20. A method of reducing hypoxia induced factor (HIF-1) expression in one or both eyes of a subject involves administering a pharmaceutical composition having an effective amount of medicament for reducing blood glucose concentration of a subject, and subsequently administering electromagnetic radiation to one or both eyes of the subject using the medical apparatus described above. In a specific example, a single dose of a GLP-1 agonist such as exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide or tirzepatide is administered to the patient. The patient will then use the medical apparatus for a period of time every day following administration of that dose for a treatment period. The treatment period may be at least the elimination half-life of the GLP-1 agonist. The GLP-1 agonist may have an elimination halflife of at least one month, and the patient will use the medical apparatus during sleep for at least one month following administration of the dose of the GLP-1 agonist. Although the methods described above discuss the administration of a pharmaceutical composition to reduce a blood glucose concentration of a subject, other means of reducing a blood glucose concentration of a subject may be implemented, such as the introduction of closed-loop glucose control or calorie restricted diets. With the above-described arrangement the form factor of the facial mask is such that it can easily and comfortably be worn during sleep. With the above-described arrangement the overall wavelength range of the total light for applying to a patient’s eye(s) has been carefully tailored to suit the requirements of the retinal cells. With the above-described arrangement an apparatus is provided that provides improved treatment efficiency compared to known devices. With the above-described arrangement an apparatus is provided that reduces the accumulation of HIF-1 in the retina to slow the onset and development of diabetic retinopathy. With the above-described arrangement a kit is provided that treats hyperglycaemia and reduces, or mitigates, the accumulation of HIF-1 in the retina to slow the onset and development of diabetic retinopathy. 5 It will be clear to a person skilled in the art that features described in relation to any of the embodiments described above can be applicable interchangeably between the different embodiments. The embodiments described above are examples to illustrate various features of the invention. 10

Claims

1. A kit of parts comprising:a medical apparatus comprising a radiation source for emitting electromagnetic radiation towards one or both eyes of a subject, wherein the medical apparatus is configured to emit electromagnetic radiation at a wavelength from 475 nm to 510 nm; anda pharmaceutical composition comprising an effective amount of medicament for use in reducing a blood glucose concentration of the subject.

2. The kit of parts according to claim 1, wherein the medical apparatus is configured to emit electromagnetic radiation at a wavelength from 495 nm to 505 nm.

3. The kit of parts according to claim 1 or claim 2, wherein the medical apparatus comprises a facial mask.

4. The kit of parts according to any preceding claim, wherein the pharmaceutical composition is provided in the form of a tablet, a capsule, a powder, a pellet for subcutaneous implantation, or a patch.

5. The kit of parts according to any preceding claim, further comprising a vial or a container comprising the pharmaceutical composition.

6. The kit of parts according to any preceding claim, further comprising a dispensation device, such as a pre-filled syringe or an infusion pump, wherein the dispensation device comprises the pharmaceutical composition.

7. The kit of parts according to any preceding claim, further comprising instructions to administer the pharmaceutical composition to the subject and subsequently use the medical apparatus to administer electromagnetic radiation to one or both eyes of the subject.

8. The kit of parts according to any preceding claim, further comprising a device comprising a controller and a user interface, wherein the device is configured to receive an input indicating administration of the pharmaceutical composition and subsequently to output one or more alerts to prompt the subject to use the medical apparatus.

9. A package comprising the kit of parts according to any preceding claim.

10. A medicament for use in the treatment of hyperglycaemia in a subject, wherein the medicament is administered to the subject and wherein electromagnetic radiation having a wavelength from 475 nm to 510 nm to one or both eyes of the subject is subsequently administered.

11. A medicament for use in the treatment of hyperglycaemia in a subject receiving concurrent treatment for retinopathy, wherein the concurrent treatment for retinopathy comprises the administration of electromagnetic radiation to one or both eyes, wherein the electromagnetic radiation has a wavelength from 475 to 510 nm.

12. A method of reducing hypoxia induced factor (HIF-1) expression in one or both eyes of a subject, the method comprising administering a pharmaceutical composition comprising an effective amount of medicament for reducing blood glucose concentration of the subject, and subsequently administering electromagnetic radiation to one or both eyes of the subject, the electromagnetic radiation having a wavelength from 475 nm to 510 nm.

13. A method for the prevention of excessive hypoxia inducible factor 1 (HIF-1) expression in one or both eyes arising in the treatment of a subject with hyperglycaemia, the method comprising:administering a pharmaceutical composition comprising an effective amount of medicament for reducing blood glucose concentration in the subject and thereby increasing HIF-1 expression in one or both eyes of the subject by a predetermined amount; andadministering electromagnetic radiation to one or both eyes of the subject, the electromagnetic radiation having a wavelength from 475 nm to 510 nm, in an amount effective to reduce HIF-1 expression by the predetermined amount.

14. The method according to claim 13, wherein the step of administering electromagnetic radiation to the one or both eyes of the subject is subsequent to the step of administering the pharmaceutical composition.

15. The medicament or the method according to any of claims 10 to 14, wherein the electromagnetic radiation administered to the one or both eyes has a wavelength from 495 to 505 nm.

16. The medicament or the method according to any of claims 10 to 15, wherein the electromagnetic radiation is administered to one or both eyes of the subject during sleep.

17. The medicament or the method according to claim 16, wherein the electromagnetic radiation is administered to one or both eyes of the subject during sleep for a period substantially equal to the elimination half-life of the medicament.

18. The kit of parts, the package, the medicament, or the method according to any of claims 1 to 17, wherein the medicament comprises one or more of a biguanide, a DPP-4 inhibitor, a thiazolidinedione, an incretin, a GIP analogue, a thiazolidinedione, a sulfonylurea, a SGLT-2 antagonist, a GLP-1 agonist or a selective mineralocorticoid receptor antagonist.

19. The kit of parts, the package, the medicament, or the method according to claim 18, wherein the medicament is a GLP-1 agonist.

20. The kit of parts, the package, the medicament, or the method according to claim 19, wherein the GLP-1 agonist is selected from the group comprising exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide and tirzepatide.

21. A method of treating, preventing, or ameliorating diabetic retinopathy or one or more symptoms of or conditions related to diabetic retinopathy, comprising:administering a medicament to a patient, wherein the medicament reduces a blood glucose concentration of the patient; and thenirradiating one or both eyes of the patient with electromagnetic radiation at a wavelength of 475 nm to 510 nm,wherein the patient is a patient diagnosed with or exhibiting symptoms of or a condition related to diabetic retinopathy.

22. The method of claim 21, the method resulting in a reduction of expression and / or accumulation of a hypoxia induced factor (HIF-1) in one or both eyes of the patient.

23. The method of claim 21, wherein the irradiating is carried out for about from 0.5 to 12 hours.

24. The method of claim 21, wherein the medicament comprises at least one of:5 biguanide, a DPP-4 inhibitor, a thiazolidinedione, an incretin, a GIP analogue, a thiazolidinedione, a sulfonylurea, a SGLT-2 antagonist, a GLP-1 agonist and a selective mineralocorticoid receptor antagonist.

25. The method of claim 21, wherein the irradiating is carried out for a time period10 equal to about an elimination half-life of the medicament.IntellectualPropertyOfficeApplication GB2408175.4Search report under Section 17 of the Patents Act 1977Date search completed: 13 November 2025Claims searched: 1-11 and 15-20 in partInternational classificationSubclass and subgroup Valid from A61K9 / 00 01 / 01 / 2006 A61N5 / 00 01 / 01 / 2006 A61N5 / 06 01 / 01 / 2006Field of searchWorldwide search of patent documents classified in the following areas of the IPC:A61N, A61K, A61PDatabases used in the preparation of this search report:SEARCH-PATENTDocuments considered to be relevantPatent literatureCategory Relevant Document of relevanceclaimsIntellectual Property Office is an operating name of the Patent Officewww.gov.uk / ipoA - CN 119258408 A GUANGBO INFORMATION TECH SHENZHEN CO LTD, Please see whole document. A - US 10888709 B2 HILL et al., Please see whole document. A - US 2023 / 0166072 A1 MALCHANO et al., Please see whole document. A - US 2014 / 0005757 A1 ENGLISH et al., Please see whole document. A - US 2017 / 0333729 A1 OLCESE, Please see whole document. Non-patent literature Category Relevant claims Document of relevanceCategoriesLetter or symbol Description X Document indicating lack of novelty or inventive step.Y Document indicating lack of inventive step, if combined with anotherdocument of the same category.Letter or symbol Description & Member of the same patent family. A Document indicating technological background. P Document published on or after the priority date but before the fling date of the present application. E Earlier application published on or after the filing date of the present application.

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