CoQ10 FOR USE IN THE TREATMENT OF MITOCHONDRIAL DYSFUNCTION IN NEUROLOGICAL DISORDERS

Abstract

The present invention relates to CoQ10 for use in the preventive and / or therapeutic treatment of a condition associated with mitochondrial dysfunction in the central nervous system of a human subject, wherein CoQ10 is being delivered to the central nervous system of a human subject via intranasal administration of CoQ10.

Description

[0001] P2607PC00

[0002] 1

[0003] CoQlO FOR USE IN THE TREATMENT OF MITOCHONDRIAL DYSFUNCTION IN NEUROLOGICAL DISORDERS

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to CoQlO for use in the preventive and / or therapeutic treatment of a condition associated with mitochondrial dysfunction in the central nervous system of a human subject.

[0006] BACKGROUND

[0007] Mitochondria are sub-cellular organelles that have a key role in the metabolism of all cell types. In addition to their role in cellular energy generation via oxidative phosphorylation, mitochondria also have roles in free radical metabolism and redox homeostasis, lipid and nucleic acid metabolism, calcium homeostasis, cell signalling, and apoptosis. Given the key role of mitochondria in normal cell metabolism, mitochondrial dysfunction has been implicated in the pathogenesis of a wide range of disorders, including neurological disorders.

[0008] The brain uses more energy than any other organ, accounting for approximately 20% of the total body energy requirement. To provide the energy required, brain tissue contains high levels of mitochondria, which are found in all brain cell types. Thus, any damage to mitochondria will result in a decreased cellular energy supply. In addition, such damage will lead to increased free radical production and calcium dysregulation, accompanied by leakage of mitochondrial components, particularly mtDNA, into the cell body activating the immune system and resulting in inflammation.

[0009] Mitochondrial dysfunction is a common factor known to be involved in the pathogenesis of a number of both common neurological disorders, such as Parkinson's disease (PD) and Alzheimer's disease, and less common disorders, such as amyotrophic lateral sclerosis (ALS) and multisystem atrophy (MSA), and progressive supranuclear palsy (PSP). Another significant neurological disorder is traumatic brain injury (TBI), resulting from head trauma and leading to severe neurological impairment or even death. TBI is commonly caused by falls, vehicle accidents, sports injuries, or violence, and involves two pathological processes: primary brain injury and secondary brain injury. Ischaemia plays an important role in both primary and secondary brain injury and can lead to mitochondrial dysfunction, contributing to oxidative stress and inflammation in the pathogenesis of brain injury, e.g. following head trauma. Existing treatment options are limited in their effectiveness, particularly for moderate to severe TBI cases. Other relevant neurological disorders include encephalopathy, seizure, migraine, stroke-like episodes, ataxia, spasticity, chorea, and dementia.P2607PC00

[0010] 2

[0011] Coenzyme Q10 (CoQlO), also known as ubiquinone, ubiquinol or Q10, is a naturally occurring coenzyme and an antioxidant produced by the human body. CoQlO is a component of the mitochondrial electron transport chain (ETC), where it plays a role in oxidative phosphorylation. In addition to acting as an antioxidant, CoQlO is also able to directly modulate the action of genes involved in inflammation and may have a role in controlling the release of pro-inflammatory cytokines. CoQlO is present in all regions of the healthy human brain, in amounts of 2-20 pg / g wet weight. Deficiency of CoQlO has been shown in, for example, the cerebral cortex in PD patients, and cerebellar tissue in MSA patients.

[0012] The key roles of CoQlO in promoting normal mitochondrial function and as an antioxidant and antiinflammatory agent thus provided a rationale for using supplemental CoQlO in the management of mitochondrial dysfunction. Particularly, the deficiency of CoQlO reported in a number of neurological disorders provided a further rationale for investigating the potential therapeutic role of supplementary CoQlO in the treatment of neurological disorders.

[0013] In previous studies, administration of CoQlO has been shown to reduce biomarkers of inflammation and oxidative stress in animal models of TBI. Likewise, administration of CoQlO has been shown to reduce brain mitochondrial damage, tissue damage, and apoptosis in animal models of TBI. However, even though corresponding studies in animal models have shown therapeutic promise, clinical trials of supplementing CoQlO in a number of neurological disorders have resulted in disappointing outcomes (Mantle D, Lopez-Lluch G, Hargreaves IP. Coenzyme Q10 metabolism: A review of unresolved issues. Int J Mol Sci. 2023;24(3):2585. doi: 10.3390 / ijms24032585).

[0014] A major obstacle to the successful delivery of therapeutic drugs to the central nervous system seems to be the blood-brain barrier (BBB). The disappointing clinical trial results of supplementing CoQlO may therefore have been related to the inability of CoQlO to cross the BBB in humans.

[0015] Studies in animal models have indicated that CoQlO may be able to cross the BBB in the trial animals (mice). However, because of differences in human and rodent anatomy, the use of a mouse model is not appropriate for studying intranasal administration of Q10 in humans. Indeed, evidence suggesting that CoQlO may be able to cross the BBB in human subjects has not been established in clinical studies.

[0016] The human blood-brain barrier (BBB) is a major obstacle to the successful delivery of therapeutic drugs to the central nervous system. Although a restricted class (molecular weight <400 Da) of lipid-P2607PC00

[0017] 3

[0018] soluble drugs are able to freely access the BBB, the latter prevents 98% of small and 100% of large molecules from entering the brain.

[0019] Delivery of CoQlO to the central nervous system of humans therefore remains a major obstacle for interventions aimed at treating conditions associated with mitochondrial dysfunction in the central nervous system of human subjects, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, progressive supranuclear palsy and traumatic brain injury brain and / or oxidative stress and inflammation in brain tissue, e.g. related to the pathogenesis of brain injury following head trauma.

[0020] Thus, there is a need in the art for innovative therapies capable of reducing and ameliorating mitochondrial dysfunction in the central nervous system (CNS) of humans, in particular for neurological disorders, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, progressive supranuclear palsy, and traumatic brain injury.

[0021] WO 2019 / 084543 Al discloses a method for treating a central nervous system disorder by intranasal administration of an effective amount of an antioxidant to a subject. The preferred effective amount of antioxidant is stated as being from 0.01 to lOmg / kg. Co-enzyme Q10 (CoQlO) is mentioned as an antioxidant.

[0022] US 2004 / 034107 Al discloses the use of intranasally administered CoQlO (ubiquinone) in the treatment of migraine. CoQlO is provided in the form of an oral or nasal spray at a dose of 20 mg up to about 1.000 mg in a single dose. Aqueous colloidal dispersion is particularly preferred.

[0023] US 2005 / 019268 Al discloses a spray containing CoQlO in an aqueous colloidal dispersion for use in the treatment of Alzheimer's disease, Parkinson's disease, or cerebral palsy by intranasal administration. Preferred dosing is disclosed to be 20 mg to about 1.000 mg in a single dose.

[0024] IT RM 990 775 Al discloses the use of CoQlO in water-soluble form by intranasal administration in the treatment of Alzheimer's disease or amyotrophic lateral sclerosis. It is disclosed that the intranasal administration of a CoQlO dispersion in water increases the concentration of CoQlO in the brain of mice.

[0025] WO 02 / 085297 A2 describes dry powder inhaler formulations comprising e.g. Q10 and substantial amounts of lactose carrier (see examples 19-20) for the treatment of lung conditions. While these formulations may be administered both orally and intranasally, the presence of lactose carrierP2607PC00

[0026] 4

[0027] material aimed at distribution of drug in the lungs obviate that these compositions are not suited for delivery of Q10 to the CNS.

[0028] Thus, the cited prior art in general discloses intranasal delivery of Q10 as aqueous dispersions at high proposed doses of Q10 and lacks disclosure of the dosing and formulation required to intranasally deliver effective treatment to the CNS of human subjects.

[0029] One object of the present invention was therefore to identify suitable methods, dosing regimens and compositions for delivery of CoQlO to the central nervous system of a human being for treating conditions in the central nervous system related to mitochondrial dysfunction, in particular in neurological disorders, as well as conditions associated with primary mitochondrial deficiency in the central nervous system.

[0030] DESCRIPTION OF THE INVENTION

[0031] It is an object of the present invention to provide improved treatments of neurological disorders associated with mitochondrial dysfunction in the central nervous system, in particular neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, progressive supranuclear palsy, and traumatic brain injury.

[0032] A further object of the present disclosure is to provide methods, dosing regimens and compositions for delivering therapeutically effective amounts of CoQlO to the central nervous system of human subjects.

[0033] As indicated in the examples below, the inventors surprisingly discovered that delivery of CoQlO to the CNS of humans may be accomplished via an intranasal route.

[0034] The delivery of drugs directly to the CNS via an intranasal route represents a non-invasive method for bypassing the BBB, essentially free of adverse effects.

[0035] The interior of the nose is divided into several regions, the olfactory and respiratory regions being the most important with regard to intranasal drug delivery. The first step in drug absorption from the nasal cavity is to cross the mucus layer. Thus, it is believed to be critical for intra nasal delivery that candidate drugs are permeable to the nasal mucosa. Small (<lkDa) lipophilic molecules may pass through the mucus layer. The drug then needs to access the nasal epithelial layer, e.g. via transcellular diffusion, paracellular transport, endocytic vesicle-mediated transport, and carrier-P2607PC00

[0036] 5

[0037] mediated transport. Transcellular diffusion is the main mechanism of absorption and is the most likely for lipophilic and low molecular weight molecules. CoQlO is a highly lipophilic substance with a molecular weight of 863Da, facilitating access across both the mucus layer and epithelial layer.

[0038] The olfactory and respiratory epithelia are innervated by the olfactory and trigeminal nerves respectively, which provide a route for drugs to access the CNS directly. Intranasal drug delivery to the central nervous system may therefore sometimes be facilitated by the olfactory and trigeminal nerves. The olfactory and trigeminal pathways are the only routes by which the CNS is connected to the outside environment. Transport of drugs via these pathways can occur via two mechanisms: intracellular and extracellular.

[0039] In the intracellular mechanism, the drug is taken up by neurons through a process of endocytosis, then transported within the nerves by axonal transport to the pons region of the brainstem (and then to the cerebrum and cerebellum) with respect of the trigeminal nerve, and to the olfactory bulb and frontal cortex with respect of the olfactory nerve, where the drug is exocytosed.

[0040] The extracellular pathway directly transports drug molecules via diffusion into the paracellular space of the nasal epithelium and then through the perineural space to the subarachnoid space of the brain. In both cases, the drug travels through the cribriform plate, which separates the CNS from the nasal cavity. The extracellular mechanism particularly allows for rapid transit of drugs, typically taking 2-3 minutes to reach the brain.

[0041] It must be anticipated that intranasal drug delivery to the central nervous system facilitated by the olfactory and trigeminal nerves has certain limitations in terms of amounts of drug being able to travel through the nerves and enter the central nervous system. Thus, whether intranasal delivery is suitable for delivering adequate amounts of the drug in question in order to elicit the desired response is difficult to predict.

[0042] Surprisingly, however, the present inventors found that delivery of CoQlO directly to the central nervous system of a human being via an intranasal route may represent a non-invasive method for CoQlO to possibly bypass the BBB and deliver adequate amounts of CoQlO to the central nervous system for treating several conditions in the central nervous system. Initially, this finding was indicated by the experiences of the inventors described in the case study in example 1 below.P2607PC00

[0043] 6

[0044] DETAILED DESCRIPTION OF THE INVENTION

[0045] As indicated in the examples below, preliminary data suggests that CoQlO is sufficiently permeable to the nasal mucosa to allow for delivery of CoQlO to the human central nervous system at doses believed to be meaningful in the preventive or therapeutic treatment of conditions associated with mitochondrial dysfunction in the central nervous system.

[0046] The present invention thereby offers an innovative approach for treating mitochondrial dysfunction in the central nervous system.

[0047] Diseases involving mitochondrial dysfunction in the central nervous system

[0048] Mitochondrial dysfunction is involved in number of neurological diseases in the central nervous system. Such diseases include diseases resulting in inflammatory conditions in the central nervous system, such as e.g. Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, progressive supranuclear palsy, and traumatic brain injury (TBI).

[0049] Primary mitochondrial deficiency disorders are a clinically heterogeneous group of disorders and diseases that arise as a result of dysfunction of the mitochondrial respiratory chain. Primary mitochondrial disorders in the central nervous system are associated with e.g. fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity as well as chorea and dementia. Primary mitochondrial deficiency diseases affect more than 1 in 5000 people.

[0050] As mentioned above, several animal studies have demonstrated changes in mitochondrial morphology following TBI and have indicated that administration of CoQlO (200 mg / kg for 7 days prior to injury) and CoQlO analogues reduced brain mitochondrial damage, apoptosis, and serum biomarkers of TBI severity, and decreased markers of brain tissue oxidative stress and enhanced neurological and cognitive functions post-injury.

[0051] Such diseases may be prevented and / or treated according to the present invention.

[0052] Thus, in a first aspect, the present invention relates to a method for delivering CoQlO to the central nervous system of a human subject in need thereof, said delivery being facilitated by intranasal administration of CoQlO. In particular, the invention thus relates to CoQlO for use in the preventive and / or therapeutic treatment of a condition associated with mitochondrial dysfunction in the central nervous system of a human subject, wherein CoQlO is being delivered to the central nervous system of a human subject via intranasal administration of CoQlO.P2607PC00

[0053] 7

[0054] This aspect of the invention also relates to a method of preventing and / or treating a condition associated with mitochondrial dysfunction in the central nervous system of a human subject, wherein CoQlO is being delivered to the central nervous system of a human subject via intranasal administration of CoQlO.

[0055] In a preferred embodiment, the conditions associated with mitochondrial dysfunction in the central nervous system of a human subject are selected among Parkinson's disease and Alzheimer's disease.

[0056] In another preferred embodiment, the conditions associated with mitochondrial dysfunction in the central nervous system of a human subject are selected among dementia, migraine, and traumatic brain injury.

[0057] In a highly preferred embodiments, the conditions associated with mitochondrial dysfunction in the central nervous system of a human subject is traumatic brain injury.

[0058] CoQlO

[0059] CoQlO may be provided from a commercial source or may be produced according to methods disclosed in the art. Preferably, the fluid formulation of CoQlO according to the present invention is produced according to the principles disclosed in example 1 of EP 3 191 444 Bl in the name of Pharma Nord ApS.

[0060] Dosing

[0061] Preferably, according to the invention, CoQlO is administered intranasally at a dose in the range of 0.1 mg - 10 mg. More preferably, CoQlO is administered intranasally at a dose in the range of 0.5 - 5.0 mg, preferably 0.5 - 2 mg, most preferably 1 mg.

[0062] Thus, a preferred daily dose is in the range of 0.5 - 5.0 mg, preferably 0.5 - 2 mg, more preferably 1 or 2 mg per day.

[0063] Administration form and volume

[0064] Candidate drugs for intranasal delivery are, preferably dissolved in a vehicle solvent, i.e. in a fluid formulation meeting the clinical criteria for safe delivery.

[0065] Thus, CoQlO is preferably administered intranasally in a fluid formulation comprising 5-200 pl.P2607PC00

[0066] 8

[0067] Preferably, CoQlO is administered intranasally in a fluid formulation comprising 10-150 ml, such as 20 - 100 pl. More preferably, CoQlO is administered intranasally in a fluid formulation comprising 10-30 ml. Even more preferably, CoQlO is administered intranasally in a fluid formulation comprising 18-22 pl, most preferably 20 pl. The required dose may be divided in 2 and administered to each nostril of the human subject. Most preferably, a single dose is administered comprising 20 pl fluid formulation.

[0068] Accordingly, a suitable concentration of CoQlO in the fluid formulation may range between 10-1,000 mg / ml, such as 20 - 200 mg / ml, such as 30 - 100 mg / ml, most preferably 50 mg / ml.

[0069] Vehicle solvent

[0070] CoQlO is a lipophilic molecule.

[0071] Aqueous dispersions have been proposed as preferred delivery vehicles for intranasal delivery of Q10 in the prior art. Indeed, aqueous dispersions proposed as preferred delivery vehicles for intranasal delivery of Q10 in the prior art aim at delivery of Q10 molecules in other target compartments such as the lungs.

[0072] However, the present inventors found aqueous dispersions to be less suited for delivering effective amounts of Q10 to the CNS of human subjects. Although evidence from rodents suggest suitability of aqueous dispersions in delivering Q10 to the brain of mice, the present inventors found that such dispersions are not suited in humans according to the present invention, as sufficient uptake of Q10 via the trigeminal / olfactory nerve pathway seems to require the CoQlO to be dissolved (or at least partly dissolved) in a solvent.

[0073] Thus, in a preferred embodiment of the present invention, the CoQlO is dissolved in an oil, preferably a vegetable oil.

[0074] Vegetable oils have been used as vehicles for intranasal delivery of lipophilic drugs because of their high solubilising capacity. Consequently, a preferred fluid vehicle for intranasal delivery of CoQlO is an oil, preferably a vegetable oil. Suitable vegetable oils are known to the person skilled in the art and may e.g. be selected among coconut oil, corn oil, cottonseed oil, canola oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil.P2607PC00

[0075] 9

[0076] The safety of soybean oil as a vehicle for intranasal drug delivery of indomethacin has been described in a preclinical model. Thus, in a preferred embodiment, the fluid formulation consists of soybean oil.

[0077] In a second aspect, the present invention relates to a unit dose formulation of CoQlO for intranasal delivery comprising 0.5 - 5.0 mg, preferably 0.5-2 mg, most preferably 1 mg CoQlO.

[0078] Preferably, the CoQlO is dissolved in a vegetable oil, preferably soybean oil, at a concentration of 30 - 100 mg / ml, most preferably 50 mg / ml. The preferred unit dose formulation of CoQlO for intranasal delivery comprises 10 - 30 pl.

[0079] Dosing regimen

[0080] The dosing preferably consists of a daily dose of the unit dose formulation according to the invention. Preferably, the dose is administered daily for at least 30 days. Even more preferably, the dose is administered daily for at least 90 days before medical evaluation. Lifelong treatment is an option.P2607PC00

[0081] 10

[0082] EXAMPLES

[0083] Example 1 — case study

[0084] Pharma Nord was contacted by a subject suffering from neurological dysfunction. The person reported that following oral administration of a CoQlO supplement, he had repeatedly experienced a reflux reaction followed by an unexpected, rapid (within 2-3 minutes) beneficial response in terms of both mood and cognition.

[0085] This phenomenon was repeatable after each intake of the CoQlO supplement.

[0086] Given the time required for CoQlO to transit the digestive system and access the bloodstream, the present inventors speculated that the only way such a rapid response might be possible would be if the CoQlO was being refluxed, absorbed from the mouth and thereby - likely via the trigeminal nerve - reaching the brain of the subject directly via the trigeminal / olfactory nerve pathway.

[0087] Although the observed phenomenon seemed to be the result of a particular physiology and / or an abnormal reaction to the CoQlO supplement related to this subject's physiology, the inventors were triggered to investigate if there could be a potential for a more general application of CoQlO via intranasal administration using a more targeted administration procedure as described in the present application.

[0088] Example 2 — CoQlO formulation for intranasal delivery

[0089] i solution of CoQlO in soybean oil was prepared at a concentration of 50 mg / ml as described by Estevez et al., 2012 (Estevez PN, Tripodi V, Buontempo F, Lucangioli S, Coenzyme Q10 stability in pediatric liquid oral dosage formulations. Farm Hosp. 2012 Nov-Dec;36(6):492-7. doi: 10.7399 / FH.2012.36.6.55). Under these conditions, the solution was stable at room temperature for at least 100 days. The drug was administered at a dose of 1 mg, using a nasal spray device, delivering lmg of CoQlO in a solvent volume of 20ul. A volume of 20ul is considered the optimal volume for intranasal drug delivery of CoQlO.

[0090] Example 3 — CoQlO penetration of nasal mucosa

[0091] Preliminary results confirming the capacity of CoQlO dissolved in an oil for penetrating nasal mucosa were obtained using an in vitro cell-based model.P2607PC00

[0092] 11

[0093] As noted above, the case study results and the molecular characteristics (high lipophilicity, molecular mass< 1000 Da) of CoQlO suggest that intranasal delivery of therapeutically effective amounts of CoQlO to the CNS of a human is feasible. Further experimental support on the ability of CoQlO to cross the nasal epithelial barrier, using a human nasal epithelial cell culture system, is planned.

[0094] Example 4 — preliminary clinical trial

[0095] Clinical studies are planned in collaboration with clinical colleagues for delivery of CoQlO via the intranasal route to patients suffering from a neurological disorder, such as Parkinson's disease and ALS. The currently proposed CoQlO dosing is at a daily dose of 2 mg in 20 pl soybean oil for at least 30 days.

Claims

P2607PC0012CLAIMS1. CoQlO for use in the preventive and / or therapeutic treatment of a condition associated with mitochondrial dysfunction in the central nervous system of a human subject, wherein CoQlO is being delivered to the central nervous system of a human subject via intranasal administration of CoQlO at a dose in the range of between 0.5 - 5.0 mg, preferably 0.5-2 mg, more preferably 1 or 2 mg.

2. CoQlO for use according to claim 1, wherein the conditions associated with mitochondrial dysfunction in the central nervous system of a human subject is a neurological disorder selected among Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, progressive supranuclear palsy, encephalopathy, seizure, dementia, migraine, stroke-like episodes, ataxia, spasticity, chorea, dementia and traumatic brain injury.

3. CoQlO for use according to claim 2, wherein the conditions associated with mitochondrial dysfunction in the central nervous system of a human subject is traumatic brain injury.

4. CoQlO for use according to any one of claims 1 to 3, wherein Q10 is administered intranasally at a dose in the range of between 0.5-2 mg, more preferably 1 or 2 mg.

5. CoQlO for use according to any one of claims 1 to 4, wherein Q10 is administered intranasally in a fluid formulation comprising 5-100 pl.

6. CoQlO for use according to claim 5, wherein Q10 is administered intranasally in a fluid formulation comprising 10-30 pl.

7. CoQlO for use according to claim 5, wherein Q10 is administered intranasally in a fluid formulation comprising 18-22 pl, preferably 20 pl.

8. CoQlO for use according to any one of claims 1 to 4, wherein Q10 is administered intranasally as a spray powder.

9. Unit dose formulation of CoQlO for intranasal delivery comprising 0.5 - 5.0 mg, preferably 0.5-2 mg, most preferably 1 or 2 mg CoQlO.

10. Unit dose formulation of CoQlO for intranasal delivery according to claim 10, comprising 10 -

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