Inclusion complex comprising a p2x7 receptor antagonist and a cyclodextrin

Abstract

The present invention relates to compositions for use in the treatment of chronic, persistent or hyperinflammation and to methods for the treatment of chronic, persistent or hyperinflammatory conditions both of which involve prolonged or excessive inflammation, such as those experienced post an infection, particularly a viral infection, or following an autoimmune disease. An inclusion complex of lidocaine and cyclodextrins is demonstrated to provide therapeutic benefit, both causal and symptomatic, in Long COVID patients.

Description

COMPOSITION AND METHOD OF TREATMENT INTRODUCTION

[0001] The present invention relates to compositions for use in the treatment of chronic, persistent or hyperinflammation and to methods for the treatment of chronic, persistent or hyperinflammatory conditions both of which involve prolonged or excessive inflammation, such as those experienced post an infection, particularly a viral infection, or following an autoimmune disease.

[0002] Chronic inflammation is a prolonged inflammatory response where the body's immune system remains active for extended periods, potentially leading to tissue damage and contributing to various chronic diseases.

[0003] Hyperinflammation or a hyperinflammatory syndrome is a known phenomenon in the medical art and is a symptom of a vast plurality of diseases resulting in dramatic if not lethal effects for the patient. The term ‘hyperinflammation’ as used herein is defined by the following 6 criteria (Webb et al., Lancet Rheumatol 2020, 2, (12) 754-763): 1) Fever, defined as a temperature of more than 38.0 °C; 2) Macrophage activation, defined as a ferritin concentration of 700 μg / l or more; 3) Haematological dysfunction, defined as a neutrophil to lymphocyte ratio of 10 or more or both haemoglobin concentration of 9.2 g / dl or less and platelet count of 110 × 10⁹ cells / L or less; 4) Coagulopathy, defined as a D-dimer concentration of 1.5 μg / ml or more; 5) Hepatic injury, defined as a lactate dehydrogenase concentration of 400 U / L or more, or an aspartate aminotransferase concentration of 100 U / L or more; and 6) Cytokinaemia, defined as an interleukin-6 concentration of 15 pg / ml or more, or a triglyceride concentration of 150 mg / dl or more, or a CRP concentration of 15 mg / dl or more.

[0004] More particular the treatment is for a condition commonly referred to as Long COVID and associated conditions as set out below.

[0005] Long COVID is a term broadly defined as signs, symptoms, and conditions that continue or develop after initial SARS-CoV-2 infection. The signs, symptoms, and conditions are present four weeks or more after the initial phase of infection, may be multi- systemic, and may present with a relapsing / remitting pattern and progression or worsen over time, with the possibility of severe and life-threatening events even months or years after infection. Long COVID is not one condition. It represents many potentially overlappingentities, likely with different biological causes and different sets of risk factors and outcomes.

[0006] Post-COVID-19 conditions is equivalent to the lay term Long COVID, and is used to describe the new, returning, or ongoing health problems people can experience four or more weeks after initial infection with the SARS-CoV-2 virus, the virus that causes COVID- 19.

[0007] Post-acute Sequelae of SARS CoV-2 infection is a term used in the scientific and medical communities that refers to ongoing, relapsing, or new symptoms or other health effects occurring after the acute phase of SARS-CoV-2 infection.

[0008] The term Long COVID as used herein covers all such terms.

[0009] More particularly the composition comprises a P2X7 receptor antagonist, more particularly still lidocaine, and most particularly it’s HCl salt together with a cyclodextrin, more particularly a β cyclodextrin and most particularly a hydroxy propylated β cyclodextrin (HPBCD). BACKGROUND

[0010] The use of a P2X7 receptor antagonist and more particularly lidocaine to treat COVID-19 (and long COVID) has been proposed.

[0011] WO2021 / 201680 (October 2021) teaches the use of lidocaine in the treatment of hyperinflammatory syndrome and more particularly the use of forms including microneedles and invasive administrative methods including intradermal, subdermal or subcutaneous administration. The content of this document is incorporated by reference.

[0012] More particularly a lidocaine infusion solution (20mg / ml) was used both intravenously and as a subdermal infusion (1mg / kg / hr) on COVID patients as was a continuous subdermal infusion (@0.5mg / kg / hr and 0.63mg / kg / hr) via a syringe pump.

[0013] WO2022 / 254363 (December 2022) discloses using lidocaine or articaine to treat COVID and long COVID by sublingual administration. The content of this document is incorporated by reference.

[0014] Whilst both these patent applications provide patient data it is apparent that many patients continue to experience post COVID symptoms – see https: / / www.thelancet.com / journals / eclinm / article / PIIS2589-5370(22)00491-6 / fulltext

[0015] Indeed, this review states that in the UK alone approx.1.8m people were reporting COVID-19 symptoms lasting more than 4 weeks as of May 2022 and in the US7.5% of adults are still experiencing persistent symptoms 3 or more months after their initial COVID-19 diagnosis.

[0016] This article concludes that “It is clear given the high prevalence of persistent symptoms after 12 weeks (nearly 1 in 2 people) that healthcare services and policy need to prioritise Long COVID care, and in addition understand different sub-types of Long COVID to permit stratified healthcare and ensure services are not overwhelmed in the future.”

[0017] With this challenge Applicant sought to provide formulations better suited to treating Long COVID as well as providing treatment regimens which are more sustainable and likely to give rise to better patient compliance. In this regard a formulation that can be self-administered and avoids a need to attend a clinic or for the patient to be hospitalised would be beneficial.

[0018] Looking to improve upon the formulations described in WO2021 / 201680 and WO2022 / 254363, formulations used to target delivery to the lymphatic system, they postulated that the use of cyclodextrins, as opposed to other generic approaches, for example, nanoparticles, microspheres, liposomes, emulsifying drug delivery systems (EDDS) and variants thereof, might be particularly attractive.

[0019] Indeed, cyclodextrins were used in delivering a number of antivirals during the pandemic. See the review article. The Role of Cyclodextrins in COVID-19 Therapy—A Literature Review. https: / / www.mdpi.com / 1422-0067 / 24 / 3 / 2974

[0020] This review confirmed the premise that β cyclodextrins might increase solubility, stability and absorption and might reduce toxicity.

[0021] To their surprise, and unexpectedly as they further reviewed the art on cyclodextrins, they discovered that for their target indication there could be additional benefits based on two lesser-known properties of cyclodextrins, namely their antiviral and anti-inflammatory properties.

[0022] In particular, Bezerra (2022) https: / / pubmed.ncbi.nlm.nih.gov / 35798224 / taught that Hydroxypropyl β cyclodextrin (HPBCD) has: i) an immunomodulatory effect (suppressing inflammatory cytokines) ii) is, independently, a therapeutic agent used in the treatment of Niemann pick C disease (where it acts to delete cholesterol); andiii) inhibits SARS-CoV2 replication.

[0023] More particularly still it reduced TNF-α levels, IL-6 and CCL2 expression such that these biomarkers might be used to identify Long COVID patients (those with high level expression) who might benefit from treatment.

[0024] Further evidence from Matasolli (2018) https: / / pubmed.ncbi.nlm.nih.gov / 30404938 / showed the treatment of monocytes from HIV infected patients with β cyclodextrin decreased TNF-α and IL 10.

[0025] To Applicants surprise they determined that cyclodextrins had been used in combination with both Lidocaine and Articane, but for different reasons. This art is discussed below in chronological order.

[0026] Moraes (2006) https: / / scholar.google.co.uk / scholar_url?url=https: / / www.academia.edu / download / 4941871 3 / s10847-006-9179-x20161006-23191 dugeey.pdf&hl=en&sa=X&ei=vMb2ZZ2DGrfHy9Ypzam kA8&scisig=AFWwaeZPoEa8iKoK0dodRYxyP5Qh&oi=scholarr discloses a lidocaine HPBCD (1:1) complex which reduces the rate of lidocaine release at a pH of 10.5.

[0027] Tatai (2007) https: / / www.researchgate.net / publication / 227089579_Preparation_and_investigation_of_m ixtures_containing_lidocaine_base_and_b-cyclodextrin taught a lidocaine base and different cyclodextrins (CD) in different ratios. It concluded that β CD was the best of eight CD derivatives and that lidocaine HCl is better for systemic applications (orally) and lidocaine base is better for dermal applications.

[0028] Suzuki (2008) https: / / link.springer.com / article / 10.1007 / s00540-008-0720-5 demonstrated that lidocaine formulated as a complex of the branched cyclodextrin 6 O -α D maltosyl β cyclodextrin could prolong local nerve block.

[0029] Soares da Silva (2011) https: / / pubmed.ncbi.nlm.nih.gov / 21822378 / disclosed a stable vaginal gel comprising lidocaine and chlorhexidine gluconate (a bactericide) with two cyclodextrins, B cyclodextrin and methyl-beta cyclodextrin lidocaine HCl.

[0030] Wei (2015) https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC4370974 / looked to address the problem of taste masking with dental lidocaine HCl injections through the use of cyclodextrins. It utilises HP BCD, not something pertinent to a subcutaneous delivery mode. The formulation further comprised a vasoconstrictor, antioxidant, chelating agent, tonicity agent and sweetener.

[0031] Ferriera (2018) https: / / academic.oup.com / jpp / article / 70 / 7 / 874 / 6121864?login=false on several cell types and

[0032] Abou-Okeil (2018) https: / / www.sciencedirect.com / science / article / abs / pii / S0014305718315519 looked at a comparison of lidocaine gel formulations with and without B cyclodextrin. They concluded an inclusion complex showed a greater decrease in inflammatory mediators.

[0033] Batista de Oliveira (2019) https: / / pubmed.ncbi.nlm.nih.gov / 30613838 / looked at whether a HPBCD lidocaine inclusion complex provided more effective in treating antinociceptive pain. The indications were in certain models it did.

[0034] Whilst there are a significant number of publications in which lidocaine has been formulated with B cyclodextrins none have been designed as injectables targeting the lymphatic system (with a profile limiting exposure to blood plasma) as set out herein, particularly where the injection site is subcutaneous tissue.

[0035] It is an object of the present invention to provide a novel dosage form of a P2X7 receptor antagonist, particularly lidocaine or articaine, as an inclusion complex with a cyclodextrin, which is presented for administration to the lymphatic system.

[0036] By presented for administration to the lymphatic system refers to an administration or delivery route wherein the majority of the receptor antagonist is delivered directly from the administration site to the lymph node, while the effective amount of the said receptor antagonist in the plasma is at least 5 times, preferably at least 10 times and morepreferably at least 15 times less than in the lymph node. In this way a therapeutically effective dose can be delivered to a patient i.e. one not limited by toxic plasma levels of 4.7µg / ml.

[0037] In other words, the levels attained at the lymph (and slowly released) are greater than 4.7 µg / ml, more preferably greater than 23.5 µg / ml, greater than 47 µg / ml and most preferably greater than 70.5 µg / ml.

[0038] The reason this is important is because in order to have an effect, the antagonist should bind the P2X7R to such an extent that the chronic, persistent or hyperinflammation, and preferably the concomitant effects are counteracted effectively. Such an effect may already be observed at a concentration of the receptor antagonist to inhibit the receptor for 10% (the so-called IC10value). The preferred inhibition is a 50% receptor inhibition, i.e. at the IC50 value. However, for P2X7R antagonists, such a concentration is above the maximal tolerable plasma level of the said antagonist which for lidocaine is about 4.7 µg / ml.

[0039] For each P2X7R antagonist, the skilled person will be aware how to determine the maximal tolerable plasma level.

[0040] However, P2X7R antagonists such as lidocaine have not been effectively used for treatment of chronic or hyperinflammation, as in order to be effective, the systemic dose needs to exceed the maximal tolerable plasma level as identified above.

[0041] The clinical evidence presented in Example 7 provides, for the first time, evidence that treatment, particularly prolonged treatment (greater than 8 weeks, more preferably more than 12 weeks through 16 to at least 24 weeks) by primary lymph node targeted administration of the said P2X7R antagonist in the said patient to a concentration in the said targeted lymph nodes that is above the maximal tolerable plasma level of the said antagonist in the said patient can provide both symptomatic and curative relief.

[0042] By primary lymph node targeting, the envisaged ICx value can be obtained in the lymph nodes, while avoiding exceeding the maximal tolerable plasma level. The inventors have found that establishing the envisaged ICxvalue in lymph nodes (which can be determined by pharmacokinetic stimulations) results in effective treatment of chronic, persistent and hyperinflammation.

[0043] Targeting lymph nodes was envisaged as it was contemplated that the lymphatic system is populated exclusively by trafficking immune cells, i.e. naïve T-cells, activated T- cells, B-cells, dendritic cells, monocytes, macrophages, neutrophils, mast cells, eosinophils, basophils and other immunologically relevant cells. It was found that by selective inhibition of the P2X7Rs of the immune cells of the lymphatic system by a P2X7R antagonist, clonal expansion of Tregs is induced. Subsequently, these Tregs migratethroughout the body exerting anti-inflammatory activity reducing systemic and (distant) local hyperinflammation.

[0044] The antagonist is administered to a concentration in the targeted lymph nodes that corresponds to the ICxfor the said receptor, the said ICxbeing above the maximal tolerable plasma level of the said antagonist in the said patient, wherein x ≥ 10, preferably ≥ 20, more preferably ≥ 30, even more preferably ≥ 40 and most preferably about 50. At IC10, 10% receptor inhibition is observed, at IC20, 20% receptor inhibition is observed, and so on. The higher x, the more receptor inhibition, the more effective the chronic, persistent or hyperinflammation is treated. It is clear to the skilled person that for a receptor antagonist that binds stronger to the receptor, the IC value will be lower than for a receptor antagonist that binds weaker to the receptor. The stronger the antagonist binds, the less amount of the said antagonist is needed to have the same effect as compared to a weaker binding antagonist.

[0045] Indeed, by constructing a pharmacokinetic model based on the physiology of the different compartments in the body where the drug is distributed, called a PBPK model [Gill, K.L et al. (2016). A Bottom-Up Whole-Body Physiologically Based Pharmacokinetic Model to Mechanistically Predict Tissue Distribution and the Rate of Subcutaneous Absorption of Therapeutic Proteins. Aaps j 18, 156-170; and De Sutter, et al. (2023). Predictive Performance of Physiologically Based Pharmacokinetic Modelling of Beta- Lactam Antibiotic Concentrations in Adipose, Bone, and Muscle Tissues. Drug Metab Dispos 51, 499-508] it is possible to predict lymph v plasma concentrations for a given drug.

[0046] A PBPK model is a way of predicting how drugs are absorbed and distributed in the body. PBPK models are used in drug development and academic research. This technology applies a computational technique that uses physiological information and the properties of the drug to simulate how drugs and their metabolites are distributed in the body [Isoherranen, N. (2024) Physiologically Based Pharmacokinetic (PBPK) Modelling of small molecules: How Much Progress Have We Made? Drug Metab Dispos]. It is therefore a powerful tool for predicting plasma, interstitial, and lymph node [Furubayashi, T., et al. (2021). Evaluation of the Pharmacokinetics of Intranasal Drug Delivery for Targeting Cervical Lymph Nodes in Rats. Pharmaceutics 13] concentrations in the absence of efficient means to measure tissue concentrations.

[0047] Using such a tool, Djo Hasan determined that, for example, 100mg lidocaine HCl – (2% w / v) could achieve a maximum lidocaine concentration in the target lymph nodes (147.23 μg / ml, achieved in 128 seconds) that were approximately 30 times the maximum tolerated plasma concentration of lidocaine (4.68 μg / ml) and remained above 10 times the tolerated plasma concentration of lidocaine for 7.96 minutes. During this period, Tregs aregenerated in these lymph nodes and migrate throughout the body to exert their systemic anti-inflammatory effect. Meanwhile, lidocaine concentrations in blood plasma, interstitium, and other lymph nodes remained well below the lower toxic levels.

[0048] The inclusion complex may comprise the lidocaine or articaine in a ratio of from 1:1 to 1:10 lidocaine or articaine to the cyclodextrin, more particularly 1: 1 to 1:8 and most preferably 1:1 to 1:6. For a small volume injection the lower ratio is preferred but there can be advantages in using ratios of up to 1:6. Hence an optimum formulation may be one of 1:2 or 1:3.

[0049] Depending on the amount of cyclodextrin it may also be desirable to include an agent to control osmolarity. A further benefit of the cyclodextrin was it reduced the viscosity of the e.g.5% lidocaine solution, enhancing injectability, improving tissue distribution, and reducing administration discomfort. This physical modification enables effective “at-home self-administration”, a key advantage over clinic-based infusions. The improved physical properties also lead to more consistent absorption and therapeutic effect between doses.

[0050] Interestingly both lidocaine and articaine additionally provide antimicrobial benefits. BRIEF SUMMARY OF THE DISCLOSURE

[0051] In accordance with a first aspect of the present invention there is provided an inclusion complex comprising: i) an active pharmaceutical ingredient (API) which is a P2X7 receptor antagonist; and ii) a cyclodextrin; for use in the treatment of an autoimmune disease or a condition in which an immune response caused by a disease or infection causes chronic, persistent or hyperinflammation wherein the inclusion complex is presented for administration to the lymphatic system.

[0052] Example P2X7 receptor antagonists in addition to lidocaine include those listed in Table 1 below: Table 1: Drug name and CAS Potency Outcome Biological effect structure number GW791343 1019779- pIC50 = Reported in04-4 6.9 – 7.2 literature AZ10606120 607378- pKd = Reported in Glioblastoma, (AstraZeneca) 18-7 8.9 = 8.7 literature antineoplastic activity AZD9056 345304- pIC50 = Phase II Inhibits iL-1B in (AstraZeneca) 65-6 8.0 – monocytes trial terminated 7.89 due to lack of Safe and well efficacy in CD or tolerated COPD CE-224,535 (Pfizer) 724424- pIC50= Phase II Safe and well 43-5 8.7 – tolerated after 12 Trial terminated 7.89 weeks of Claimed in administration patent COPD, arthritis, US6974812 asthma GSK1482160 1001389- pIC50 = Failed to reach Efficacy in (GlaxoSmithKline) 72-5 8.1 therapeutic preclinical mouse efficacy within models of pain safety margins JNJ-54175446 1627902- pIC50 = Phase II clinical Mood modulatory (Janssen) 21-9 8.46 trials (ongoing effects in healthy as of 2023, patients with NCT04116606) dexamphetamine Possible neuroinflammation treatmentAntiseizure effects JNJ55308942 2166558- pIC50 = Phase II clinical Efficacy in mouse (Janssen) 11-6 8.0 trials for Bipolar models of disorder and depression major depressive episode Backup to JNJ- Last updated 54175446 31 / 01 / 24 (NCT05328297) JNJ54173717 N / A pIC50 = Phase I clinical Radiolabelled as a (Janssen) 8.38 trials marker for neuroinflammation for patients with Parkinson’s EVT401 (Evotec) N / A pIC50 = Phase II clinical Inflammatory 8.03 trials conditions (R heumatoid Oral P2X7 arthritis) receptor antagonist Cannabidiol 13956- Reported in Exerts anti- 29-1 literature inflammatory effects in monocytes comparable to NLRP3 inflammasome inhibitors

[0053] Hyperinflammation, or an overactive inflammatory response, also chronic or persistent inflammation, is implicated in various inflammatory conditions, includingautoimmune diseases, cardiovascular diseases, gastrointestinal disorders, lung diseases, and other conditions as outline below.

[0054] A list of exemplary conditions or diseases associated with chronic inflammation, and which could benefit from treatment, including the provision of symptomatic relief, are given below: Autoimmune Diseases:

[0055] Post-Acute Infection Syndromes (PAISs): A chronic inflammatory condition following acute infection, including Long COVID.

[0056] Rheumatoid Arthritis: A chronic inflammatory condition primarily affecting the joints.

[0057] Lupus (Systemic Lupus Erythematosus): A chronic inflammatory disease that can affect various organs and tissues.

[0058] Psoriasis: A chronic inflammatory skin condition that causes red, scaly patches.

[0059] Ankylosing Spondylitis: A chronic inflammatory condition primarily affecting the spine.

[0060] Multiple Sclerosis: A chronic inflammatory disease that affects the central nervous system.

[0061] Type 1 Diabetes: An autoimmune condition where the body attacks insulin- producing cells in the pancreas. Cardiovascular Diseases:

[0062] Heart Disease: Inflammation plays a role in the development of atherosclerosis, a buildup of plaque in the arteries.

[0063] High Blood Pressure: Chronic inflammation can contribute to the development of high blood pressure. Gastrointestinal Disorders:

[0064] Crohn's Disease: A chronic inflammatory condition that can affect any part of the digestive tract.

[0065] Ulcerative Colitis: A chronic inflammatory condition that affects the large intestine.

[0066] Irritable Bowel Syndrome (IBS): Whilst the exact cause is unknown, inflammation is involved. Lung Diseases:

[0067] Asthma: A chronic inflammatory condition that affects the airways.

[0068] Chronic Obstructive Pulmonary Disease (COPD): A chronic inflammatory lung disease that causes airflow obstruction. Other Conditions:

[0069] Certain Cancers: Chronic inflammation can contribute to the development and progression of some cancers.

[0070] Alzheimer's Disease: Chronic inflammation in the brain is thought to play a role in the development of Alzheimer's disease.

[0071] Parkinson's Disease: Chronic inflammation is also linked to Parkinson's disease.

[0072] Type 2 Diabetes: Chronic inflammation can contribute to insulin resistance, a key factor in type 2 diabetes.

[0073] Depression and Anxiety: Chronic inflammation is considered to be linked to mental health conditions.

[0074] Fatty Liver Disease: Poor diet can lead to inflammation in the liver, potentially leading to cirrhosis, liver cancer, and liver failure.

[0075] A fuller list of indications is, as disclosed in WO2021 / 201680, reproduced in Appendix 1, before the claims:

[0076] In one embodiment the autoimmune disease or the condition in which an immune response caused by the disease or infection causes chronic, persistent or hyperinflammation is a post viral condition.

[0077] More particularly the post viral condition is Long COVID.

[0078] In this regard hyper inflammation often results in chronic inflammation.

[0079] Presentation to the lymphatic system most preferably comprises administration by way of intradermal, subdermal or sub-cutaneous injection, but may comprise other modes of administration including infusions, Oro mucosal delivery and transdermal delivery (micro-needles).

[0080] In one embodiment a unit dose is presented in a pen injector. Such a presentation is particularly advantageous as it allows the patient to self-medicate at home.

[0081] The pen injector typically comprises a dose volume of 5ml or less, more preferably 3ml or less, and where the P2X7 receptor antagonist is lidocaine, the lidocaine is present at a concentration (wt / vol) of at least 1%, and more preferably at least 2.5%, more preferably still at least 5% and most preferably at least 7.5%.

[0082] If using a syringe, larger volume doses may be used e.g. those holding a nominal 5ml, or 10ml volume. These may be pre-filled.

[0083] In another embodiment a unit dose is presented in an infusion pump by way of intradermal, subdermal or sub-cutaneous delivery.

[0084] The infusion pump typically comprises 5ml to 1000ml, more typically 20ml to 500ml of a solution of the inclusion complex and where the P2X7 receptor antagonist is lidocaine, the lidocaine is present at a concentration (wt / vol) of at least 0.5% and the solution is delivered at a flow rate of, for example, 1ml / kg / hr (depending on the lidocaine or articaine concentration) such that the patient attains a daily dose from 0.5mg / Kg to up to 28mg / Kg over a 24 hour period. This upper dose might be increased further by inclusion of a vasoconstrictor. Such a dosage regime would equally apply to other administration devices targeting the lymphatic system, such as the injector pen.

[0085] In the most preferred embodiments, the API is Lidocaine or a salt thereof, or Articaine or a salt thereof.

[0086] The API may be in the form of a base or a salt.

[0087] Where a salt is used, the preferred salt is the hydrochloride salt.

[0088] In a preferred embodiment the cyclodextrin is a β cyclodextrin.

[0089] A favoured β cyclodextrin is hydroxy propylated (HP) β cyclodextrin.

[0090] The inclusion complex further comprises a pH modifier.

[0091] The preferred pH modifier is an alkali.

[0092] Particularly favoured is sodium bicarbonate due to its’ mild action.

[0093] In accordance with a second aspect of the present invention there is provided a formulation comprising an inclusion complex of:i) Lidocaine HCl or Articaine HCl; and ii) Hydroxy propylated β cyclodextrin; together with iii) a pH modifier; and iv) water wherein the pH is between 5 and 7.4, i) and ii) are present in a ratio of between 1:1 and 1:6; and the concentration of i) is between 2.5% and 20% weight / volume.

[0094] More preferably the ration is between 1:1 and 1:3 e.g.1:1, 1:2 or 1:3.

[0095] The formulation has a demonstrated shelf life of at least 64 weeks based on accelerated stability testing at 60º C.

[0096] The formulation is most preferably presented for subcutaneous delivery.

[0097] A daily dose delivered in such a manner my be provided as up to 5-unit doses per day.

[0098] A daily dose may be upwards of 5mg / Kg (for a 70Kg patient = 350mg or e.g.4 x 87.5mg or 3 x 116.6mg, more preferably 7mg / Kg, through to 14mg / Kg and even up to 28mg / Kg.

[0099] In one embodiment it is presented as a small volume injectable with a volume of 5ml or less, more preferably 3ml or less and is delivered subcutaneously.

[0100] In an alternative embodiment it is provided as an infusion, to be delivered over from 1 to 30 days by way of an infusion pump.

[0101] The syringe or infusion pump delivers a therapeutic unit dose, of articaine or lidocaine, as described previously, to a patient, which dose results in a lymph dose which is considerably higher than a peak plasma level which should be below 4.7ug / ml for lidocaine to avoid toxicity.

[0102] According to a third aspect of the present invention there is a method of treating Long COVID comprising administering to a patient an effective amount of a formulation of the invention.

[0103] In accordance with a fourth aspect of the present invention there is provided Lidocaine or a salt thereof for use in the treatment of a chronic, persistent orhyperinflammatory condition wherein the lidocaine or a salt thereof is administered in a format and at a dose that targets the lymphatic system, resulting in predicted peak lymph level above 47µg / ml and a peak plasma level for lidocaine of below 4.7µg / ml.

[0104] Preferably the treatment is a causal treatment.

[0105] A causal treatment may be indicated by a statistically significant improvement in a patient determined by a health-related quality of life (HRQoL) assessment.

[0106] The assessment may indicate a physical improvement, as indicated by a physical component score (PCS) or mental improvement as indicated by a mental component score (MCS).

[0107] Alternatively, the treatment may be a symptomatic treatment.

[0108] Symptomatic treatment may provide relief of one or more of: ● Cardiovascular functioning, symptoms and conditions; ● Fatigue or exhaustion; ● Pain; ● Nervous system functioning, symptoms and conditions; ● Cognitive functioning, symptoms and conditions; ● Mental health functioning, symptoms and conditions ● Respiratory functioning, symptoms and conditions; ● Post exertion symptoms; and ● Physical functional symptoms and conditions.

[0109] Preferably the treatment provides symptomatic relief in two, three, four, five, six, seven, eight or all nine of these areas.

[0110] A cardiovascular symptom assessment may comprise assessing one or more of: heart palpitations (POTS), orthostatic dizziness and chest pain.

[0111] A fatigue or exhaustion assessment may comprise assessing one or more of: fatigue and endurance / exercise tolerance.

[0112] A pain assessment may comprise assessing one or more of: joint pain, muscle pain, pleuritic pain, cephalalgia, facial pain and pharyngalgia.

[0113] A nervous system symptom assessment may comprise assessing one or more of: dizziness, sleep disturbance, tinnitus, anosmia / ageusia, ocular problems, and hypersensitivity to sensory input.

[0114] A cognitive functioning symptom assessment may comprise assessing one or more of memory loss and concentration problems.

[0115] A mental health symptom assessment may comprise assessing a feeling of anxiety / depression.

[0116] A respiratory symptom assessment may comprise assessing dyspnoea.

[0117] A post exertion symptom assessment may comprise assessing post-exertional malaise (PEM).

[0118] A physical symptom assessment may comprise assessing one or more of: reduction in daily functioning / mobility, muscle weakness, diarrhoea, nausea / vomiting, a feverish feeling, skin abnormalities, hair loss, and changes in menstrual cycle.

[0119] In one embodiment the chronic, persistent or hyperinflammatory condition is selected from: ● Autoimmune Diseases; ● Cardiovascular Diseases; ● Gastrointestinal Disorders: ● Lung Diseases; and ● Other diseases selected from o Cancers; o Alzheimer's Disease; o Parkinson's Disease; o Type 2 Diabetes; o Depression and Anxiety; and o Fatty Liver Disease.

[0120] Where the hyperinflammatory condition is an autoimmune disease the condition may be selected from: ● Post-Acute Infection Syndromes (PAISs); ● Rheumatoid Arthritis; ● Lupus (Systemic Lupus Erythematosus); ● Psoriasis; ● Ankylosing Spondylitis; ● Multiple Sclerosis; and ● Type 1 Diabetes.

[0121] Where the hyperinflammatory condition is a Cardiovascular disease it may be selected from heart disease or high blood pressure.

[0122] Where the hyperinflammatory condition is a gastrointestinal disease it may be selected from● Irritable bowel disease; ● Crohn's disease; and ● Ulcerative colitis.

[0123] Where the hyperinflammatory condition is a lung disease it may be selected from ● Asthma; and ● COPD.

[0124] Preferably the Lidocaine or a salt thereof is in a format that targets the lymphatic system is one of invasive or topical.

[0125] Where it is invasive it is one of ● Subcutaneous; ● Intrademal; or ● Subdermal.

[0126] Where it is topical it is one of ● Oral; ● Pulmonary; ● Transdermal; or ● Nasal.

[0127] Where it is oral it is preferably ● Sub-lingual; ● Buccal; or ● Oropharyngeal.

[0128] In a particularly favoured embodiment, the Lidocaine or a salt thereof is formulated as an inclusion complex with HPBCD.

[0129] In accordance with a fifth aspect of the present invention there is provided a method of treating a subject having a chronic, persistent or hyperinflammatory condition comprising administering an effective dose of Lidocaine or a salt thereof in a format and at a dose that targets the lymphatic system, resulting in predicted peak lymph level above 47µg / ml and a peak plasma level for lidocaine of below 4.7µg / ml.

[0130] Different aspects and embodiments of the invention are further described hereinafter with reference to the detailed description.DEFINING TREATMENT

[0131] As long COVID is a new, complex and poorly understood disorder it is helpful to have a grasp of measurement instruments for use in a clinical and research setting.

[0132] A paper by Gorst et al, Lancet Respiratory Medicine 2023, vol 11, p1101-1114 discusses 12 core outcomes and a push towards a consensus to rate the instruments for each outcome using the Delphi process.

[0133] The 12 core outcomes are listed below and include 9 more specific symptom outcomes and 3 more general “wellbeing” outcomes.

[0134] The 9 more specific symptomatic outcomes, which may also be common to other chronic, persistent or hyperinflammatory conditions, as outlined hereinbefore, include: ● Cardiovascular functioning, symptoms and conditions; ● Fatigue or exhaustion; ● Pain; ● Nervous system functioning, symptoms and conditions; ● Cognitive functioning, symptoms and conditions; ● Mental health functioning, symptoms and conditions; ● Respiratory functioning, symptoms and conditions; ● Post exertion symptoms; and ● Physical functional symptoms and conditions.

[0135] The 3 more general “wellbeing” outcomes include: ● Work or occupational study conditions; ● Multidomain; and ● Post COVID-19 condition specific.

[0136] Assessment tools / scales for each of the above outcomes include, but are not limited to:

[0137] Cardiovascular functioning, symptoms, and conditions ● Symptom Burden Questionnaire for Long COVID–circulation subscale; and ● New York Heart Association Functional Class scale.

[0138] Fatigue or exhaustion ● Fatigue Assessment Scale; ● Fatigue Severity Scale; and ● Functional Assessment of Chronic Illness Therapy–fatigue subscale.

[0139] Pain ● Brief Pain Inventory.

[0140] Nervous system functioning, symptoms, and conditions ● Central Sensitisation Inventory.

[0141] Cognitive functioning, symptoms, and conditions ● Cognitive Failures Questionnaire; and ● Montreal Cognitive Assessment–Blind version

[0142] Respiratory functioning, symptoms and conditions ● A modified MRC Dyspnoea scale.

[0143] Mental health functioning, symptoms, and conditions ● GAD-7 questionnaire; and ● PTSD Checklist for DSM-5.

[0144] Post-exertion symptoms ● DePaul Symptom Questionnaire.

[0145] Physical functioning, symptoms, and conditions ● Symptom Burden Questionnaire for Long COVID–impact on daily life subscale.

[0146] Work or occupational and study changes ● Work Ability Index; ● Work Productivity and Activity Impairment questionnaire; and ● WHO post-COVID-19 Case Report Form occupational status item.

[0147] Multidomain instruments ● EuroQol 5-Dimension 5-Level survey; ● Short Form (36) Health Survey; and ● WHO Disability Assessment Schedule 2.012-item version.

[0148] Post COVID-19 condition specific instruments ● COVID-19 Yorkshire Rehabilitation Screening Scale; and ● Symptom Burden Questionnaire for Long COVID.

[0149] A therapeutic (or causal) treatment targets the underlying cause or mechanism of the disease. Its goal is to cure the disease or slow down its progression.

[0150] In the context of the present invention “therapeutic or causal treatment” may be defined as a positive outcome in a HRQoL study. It can be physical (PCS) and / or mental (MCS).

[0151] A symptomatic treatment on the other hand seeks to relieves the symptoms or discomfort caused by the disease.

[0152] In the context of the present invention “symptomatic treatment” is defined as a positive outcome in any one or more of the outcomes above, more preferably at least two, through three, four, five, six, seven, eight and nine outcomes. The combination can be any permutation of the nine outcomes.

[0153] Such symptomatic relief, given one is treating a chronic, persistent or hyperinflammation is applicable to any disease of a chronic, persistent or hyperinflammatory nature.

[0154] A paper by L Mahoney et al eClinical medicine, The Lancet, Vol 55, 101762, January 2023 titled: The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: a systematic review and meta-analysis reviewed 194 studies and 735,006 patents identified key symptoms amongst hospitalised (Fig 2 therein) and non-hospitalised patients (Fig 3 therein).

[0155] Amongst hospitalised patients the predominant symptoms effecting over 10% of patents were in order: ● Fatigue / weakness 34.8%; ● Breathlessness (dyspnoea) 20.4%; ● Muscle pain / Myalgia 17.0%; ● Affected sleep 15.3%; and ● Smell 12.6%.

[0156] Amongst non-hospitalised patients the predominant symptoms effecting over 10% of patents were in order: ● Fatigue / weakness 25.2%; ● Breathlessness (dyspnoea) 18.2%; ● Impaired usual activity 17.4%; ● Taste 14.9%; ● Smell 14.1%; ● Depression 13.3%; ● Muscle pain / Myalgia 12.8%; ● Joint pain 12.4%; ● Affected sleep 12.0%;● Gastro-intestinal symptoms 11.7%; ● Dizziness 11.2%; ● Anxiety 10.7%; and ● Cough 10.4%.

[0157] Again, effective treatment can be considered as a statistically significantly reduction in one or more of these symptoms, particularly those effecting more than 10% of patients, more particularly more than 15% of patients and more particularly still more than 20% of patients,

[0158] Symptoms of particular significance include those common to both hospitalised and non-hospitalised patients including Fatigue / weakness, Breathlessness (dyspnoea), Muscle pain / Myalgia and Affected sleep.

[0159] More preferably treatment provides a statistically significant reduction in one, two, three or all four of these most predominant symptoms.

[0160] Other review articles making similar points include:

[0161] Natarajan et al Systemic Reviews (2023) 12:88 A systemic review and meta- analysis of long COVID symptoms which states a report from the Centre for Disease Control and Prevention (CDC) in the USA reported that patients recovering from SARS- CoV-2 have continuous symptoms of shortness of breath, fatigue, brain fog, cough, chest pain, stomach pain and headache. They categorised symptoms into 4 key categories including: ● Neurological symptoms, including cognitive impairment, ● Mental Health symptoms, including anxiety, depression, and sleep disturbance, ● Cardiopulmonary symptoms, including dyspnoea, and ● Gastrointestinal symptoms. DETAILED DESCRIPTION

[0162] The invention is further described with reference to the following Figs and Examples in which. Figs 1a-c are respectively a chromatogram of lidocaine HCl titration, concentration data and calibration curve; Fig 2a-c are respectively a chromatogram of articaine HCl titration, concentration data and calibration curve;Figs 3a-c are respectively chromatograms of lidocaine HCl titration pH adjusted and, concentration data; Fig 4 a-c are respectively chromatograms of articaine HCl titration pH adjusted and, concentration data; Figs 5a-e are respectively chromatograms for lidocaine HCl with HPBCD and 25mg / ml, 50mg / ml, 100mg / ml and 200mg / ml lidocaine HCl with HPBCD, pH adjusted; Fig 6 are respectively chromatograms for articaine HCl with HPBCD and 25mg / ml, 50mg / ml, 100mg / ml and 200mg / ml articaine HCl with HPBCD, pH adjusted; Fig 7a and 7b are respectively chromatograms of lidocaine HCl and Articaine HCl during stability testing; Figs 8a-d are respectively chromatograms for sterilised lidocaine HCL and articane HCL inclusion complexes with HPCD; Fig 9 is a graph showing the improvement in symptom burden for 8 of the 9 main symptomatic groups, each with a difference of -0.7 or more, in the Long-COVID study of the Example 7; Fig 10 is a graph showing symptomatic improvement across 30 measured symptoms in the Long-COVID study of the Example 7; and Fig 11 is a graph showing general wellbeing improvement, split into a physical component score (PCS) and mental component score (MCS), in the Long-COVID study of the Example 7.

[0163] The aim of the experiments was to firstly identify formulations (particularly excipients and pH) that would allow high concentrations of lidocaine or articaine either as the freebase or salt (HCl) to be solubilised.

[0164] A further aim was to determine the stability of the identified formulations.

[0165] Yet a further aim was to demonstrate clinically the benefit of lidocaine in treating chromic, persistent or hyperinflammatory conditions as exemplified by Long COVID. Example 1 Solubility and pH studies of API without excipients Materials and methods

[0166] Stock solutions were made of: ● Lidocaine HCl (200 mg / mL); ● Articaine HCl (200 mg / mL); and ● NaOH (0.5 M).

[0167] Lidocaine HCl and articaine HCl solutions were serially diluted. Solubility Results

[0168] The results are illustrated in Figs 1a-c and Figs 2a-c which respectively show: a) chromatogram overlay of lidocaine and articaine HCl titration; b) concentration tables; and c) calibration curves.

[0169] Following calibration, the pH of lidocaine and articaine HCl, at different concentrations, was determined as set out in Tables 2 and 3 below. Table 2 Drug conc 25 mg / mL (2.5 50 mg / mL (5 100 mg / mL (10 200 mg / mL (20 (%) %) %) %) %) Lidocaine 5.43 4.78 4.35 3.86 HCl Articaine HCl 5.33 4.51 4.04 3.84 Table 3 Drug Original pH pH pH pH acceptable pH range Lidocaine 3.86 5.2 6.03 6.8 5 – 6.8 HCl Soluble Soluble Soluble Articaine HCl 3.84 6.0 6.89 7.16 5.4 – 6.9 Soluble Soluble CloudypH Results

[0170] The results are illustrated in Figs 3 and 4 which show: a) chromatogram overlay of lidocaine / articaine HCl titration; b) concentration tables; and c) calibration curves. Example 2 Solubility and pH studies of API with cyclodextrins Materials

[0171] Formulations were made up from: API: ● Lidocaine HCl; or ● Articaine HCl (2.5, 5, 10 and 20 %). Excipient ● HPBCD; or ● Captisol™: 1:1 molar ratio. Solvent: ● Distilled water and sterilised. Method

[0172] A 40 % stock solution of API was made up was serially diluted to 5 mL for each of the desired concentrations. Subsequently, the relevant amount of cyclodextrin was added as a powder. The pH of the formulation was measured using a pH probe and subsequently adjusted using 0.5 M NaOH. The formulations were then stirred at 37 ºC in a Radley reaction tube in a reaction carousel and visually inspected after 4 hours and then 16 hours, stirring at 37 ºC. Only the lidocaine HCl formulations were analysed via HPLC – the articaine HCl formulation data may be inferred from the stability studies.Results

[0173] pH of cyclodextrins at high concentrations are illustrated in Tables 4 and 5 ● 2-hydroxypropyl beta cyclodextrin (480 mg / mL) = 5.65 ● Captisol (700 mg / mL) = 5.11 Table 4 Lidocaine HCl Conc CD Conc Lido Solubility pH pH Solubility HCl adjustment** (HPLC) HPBCD 134 mg / mL 2.5 % Clear solution, 5.56 - soluble 267 mg / mL 5 % Clear solution, 5.5 - soluble 534 mg / mL 10 % Clear solution, 4.73 5.98 Soluble soluble 1068 20 % Clear viscous 4.62 5.47 Soluble mg / mL gel, soluble Captisol 194 mg / mL 2.5 % Clear solution, 4.7 5.54 Soluble soluble 388 mg / mL 5 % Clear solution, 4.57 5.86 Soluble soluble 776 mg / mL 10 % Clear solution, 4.34 5.83 Soluble soluble 1552 20 % Clear viscous 3.98 5.58 Soluble mg / mL gel, soluble Table 5 Articaine HCl Conc CD Conc Arti Solubility pH pH Solubility HCl adjustment** (visual inspection)HPBCD 120 mg / mL 2.5 % Clear solution, - soluble 5.2 240 mg / mL 5 % Clear solution, - - soluble 4.46 480 mg / mL 10 % Clear solution, - - soluble 4.32 960 mg / mL 20 % Clear viscous 5.45 Soluble** gel, soluble 3.96 Captisol 175 mg / mL 2.5 % Clear solution, - - soluble 4.6 350 mg / mL 5 % Clear solution, - - soluble 4.39 700 mg / mL 10 % Clear solution, - - soluble 4.3 1400 20 % Clear viscous 5.78 Soluble** mg / mL gel, soluble 4.13 ** Visually inspected – chromatograms not taken however

[0174] The results are further illustrated in Figs 5 and 6. Discussion and conclusions across the lidocaine and articaine HCl studies

[0175] Initially, lidocaine and articaine HCl calibration curves were obtained up to 200 mg / mL of concentration with 2-fold serial dilutions down to 25 mg / mL. The pHs of these solutions were also assessed. From 25 – 200 mg / mL, Lidocaine HCl solutions were between the pH range 5.43 – 3.86 and the articaine HCl solutions were between pH range 5.33 – 3.84.

[0176] Lidocaine HCl and Articaine HCl are soluble in water at 200 mg / mL without excipients and may both be adjusted to at least pH 6.8 and 6.9 respectively without solubility issues.

[0177] Solubility studies with excipients cyclodextrins (HPBCD and Captisol™) were subsequently undertaken. Initially, serially diluted formulations of lidocaine HCl withstoichiometric amounts of the relevant CD were assessed by HPLC. The extensive HPLC studies were only done for lidocaine HCl. For Articaine HCl, visual inspection was undertaken. It was assumed that the results across lidocaine and articaine would be similar given they were already both soluble in water at the highest concentrations, and both excipients are used to solubilise drugs.

[0178] The chromatograms were compared across the original standards at the relevant concentrations and those with the cyclodextrins, and if relevant at the adjusted pH. The chromatograms of the lidocaine HCl at increasing concentrations were also compared. It was observed that the chromatograms of the original standards, the cyclodextrin formulations and the adjusted pH formulations were the same, barring changes in retention time due to changes in buffer.

[0179] Incremental increase in area under the curve were observed with increasing concentrations of API and cyclodextrin.

[0180] Significantly, these two observations taken together suggest that the compound and cyclodextrin formulations are soluble at increasing concentration even when the pH is adjusted thereby making high concentration aqueous formulations suitable for their intended purpose (lymphatic delivery avoiding plasma concentrations of 4.7µg / ml when delivered as an injectable).

[0181] Taken together this suggests that lidocaine and articaine HCl are soluble at high concentrations with 1:1 molar ratios of cyclodextrins at formulation pHs that are physiologically relevant.

[0182] Lidocaine and articaine HCl are soluble at 200 mg / mL in water with high concentrations of HPBCD (~ 1000 mg / mL) and Captisol™ (~ 1552 mg / mL) at pH range around 5 – 6.9. Example 3 Lidocaine and articaine freebase studies Solubility and pH studies without excipients Materials ● Lipophilic lidocaine (500 mg) 1M HCl. ● Lipophilic articaine (500 mg)1M HCl.Method

[0183] The relevant lipophilic API was added to a Radley tube and 5 mL of distilled water was added, which formed a milky suspension.1M HCl was added until the suspension clarified into a solution and no more precipitate was observed. Results

[0184] ~ 2.8 mL of 1 M HCl was required to solubilise the lipophilic drugs. For lipophilic lidocaine, the pH of the resultant formulation was measured to be 1.41 and for lipophilic articaine, the pH was measured to be 1.68. Solubility and pH studies with cyclodextrins Materials

[0185] API a. Lipophilic lidocaine (1000 mg). b. Lipophilic articaine (1000 mg.)

[0186] Stock solutions: a. HPBCD (200 mg / mL). b. Captisol (200 mg / mL). Method

[0187] To 5 mL of the relevant stock solutions was added 1000 mg of either lipophilic lidocaine or lipophilic articaine to form a 20 % suspension. Subsequently 1M HCl was titrated in to 0.75 equivalents HCl, at which point the pH was taken and the formulation was visually inspected. Subsequently 1M HCl was titrated into 1 equivalent of HCl and the pH was taken and the final formulation was visually inspected. Results

[0188] The results are tabulated in Tables 6a and 6b below:Table 6a Lipophilic lidocaine (20 %) Excipients Initial formulation 0.75 eq HCl 1 eq. HCl HPBCD (20 %) Insoluble pH = 6.44 pH = 2.95** Cloudy Clear solution emulsion Captisol (20 %) Insoluble pH = 6.44 pH = 6.10 Some Clear solution precipitate remaining Table 6b Lipophilic articaine (20 %) Excipients Initial 0.75 eq HCl 1 eq. HCl formulation HPBCD (20 %) Insoluble pH = 6.53 pH = 5.82 Some Clear solution precipitate remaining Captisol (20 %) Insoluble pH = 6.60 pH = 6.44 Clear solutionSome precipitate remaining ** overshot the amount of HCl to add (titration error) Discussion and conclusions

[0189] It is possible to solubilise highly concentrated lipophilic lidocaine and articaine only if you adjust the pH of the solution to ~ pH 6.1 (equimolar HCl). This means that ~3 % of the lipophilic lidocaine and ~ 4 % of the lipophilic articaine is available in the solution, with the remainder being in the HCl salt form (calculated according to the Henderson Hasselbach equation with pH = 6.1 for lidocaine and pH = 6.44 for articaine solutions). Example 4

[0190] Formulations for stability testing were prepared as follows:

[0191] Materials were as set out in Table 7 below: Table 7 Reagent Quantity CAS # Lidocaine HCl monohydrate 4.24 g 6108-05-0 Articaine HCl 4 g 23964-57-0 2-Hydroxylpropyl-beta- cyclodextrin 16 g 128446-35-5 Sodium hydrogen 100 mg 144-55-8 carbonate (NaHCO3) Distilled H2O 100 mL 7732-18-5

[0192] 5 mL formulations containing 2.5%, 5 %, 10 % or 20 % articaine HCl or lidocaine HCl with 2.5 %, 5 %, 10 %, 20 % and 40 % 2-Hydroxylpropyl-beta-cyclodextrin (all percentages are w / v) were prepared from stock solutions.Preparation of Stock Solutions

[0193] Lidocaine HCl (400 mg / mL) 1) Take a clean 50 mL RBF on a balance and then add 4.24 g of Lidocaine HCl monohydrate 2) Add 10 mL of distilled water 3) Allow the solution to stir at 200 rpm until all the powder dissolves

[0194] Articaine HCl (400 mg / mL) 1) Take a clean 50 mL RBF on a balance and then add 4 g of Articaine HCl 2) Add 10 mL of distilled water 3) Allow the solution to stir at 200 rpm until all the powder dissolves

[0195] 2-Hydroxylpropyl-beta-cyclodextrin (800 mg / mL) 1. Take a clean 50 mL RBF on a balance and then add 16 g of 2-Hydroxylpropyl-beta- cyclodextrin 2. Add 20 mL of distilled water 3. Allow the solution to stir at 200 rpm until all the powder dissolves Preparation of 5 mL formulations 1. In clean 5 mL volumetric flasks, pipette the following volumes of the relevant stock solutions in table 2. 2. Add distilled water to all formulations to make up a final volume of 5 mL 3. Using a calibrated pH meter, measure the pH of all the formulations. 4. Add 3 – 5 mg of NaHCO3to each formulation where necessary to adjust the final pH.

[0196] The formulations which underwent stability testing (Example 5 below) are set out in Tables 8 and 9 below. Table 8 Formulation Lidocaine HCl (400 HPBCD (800 Initial pH Final pH mg / mL) mg / mL) 2.5 % 312.5 uL 156.25 uL 4.69 5.94 Lidocaine HCl2.5 % HPBCD 2.5 % 312.5 uL 312.5 uL 4.52 5.86 Lidocaine HCl 5 % HPBCD 5 % 625 uL 312.5 uL 4.99 6.07 Lidocaine HCl 5 % HPBCD 5 % 625 uL 625 uL 4.78 5.77 Lidocaine HCl 10 % HPBCD 10 % 1.25 mL 625 uL 4.44 5.70 Lidocaine HCl 10 % HPBCD 10 % 1.25 mL 1.25 mL 4.20 5.72 Lidocaine HCl 20 % HPBCD 20 % 2.5 mL 1.25 mL 3.86 5.50 Lidocaine HCl20 % HPBCD 20 % 2.5 mL 2.5 mL 3.90 6.19 Lidocaine HCl 40 % HPBCD Table 9 Formulation Articaine HCl (400 HPBCD (800 mg / mL) Initial pH Final pH mg / mL 2.5 % 312.5 uL 156.25 uL 4.93 5.66 Articaine HCl 2.5 % HPBCD 2.5 % 312.5 uL 312.5 uL 4.62 6.13 Articaine HCl 5 % HPBCD 5 % 625 uL 312.5 uL 4.40 5.84 Articaine HCl 5 % HPBCD 5 % 625 uL 625 uL 4.51 5.74 Articaine HCl10 % HPBCD 10 % 1.25 mL 625 uL 4.51 5.74 Articaine HCl 10 % HPBCD Example 5 Lidocaine and Articaine HCl salt with hydroxypropyl beta cyclodextrin stability studies

[0197] This example aimed to demonstrate the stability of 2.5%, 5 %, 10 % or 20 % Articaine HCl or lidocaine HCl with 2.5 %, 5 %, 10 %, 20 % and 40 % 2-Hydroxylpropyl- beta-cyclodextrin (HPBCD) (all percentages are w / v). Materials

[0198] The materials are set out in the Tables 10 and 11 below: Table 10 Lidocaine HCl formulations pH 2.5 % Lidocaine HCl, 2.5 % HPBCD 5.94 2.5 % Lidocaine HCl, 5 % HPBCD 5.86 5 % Lidocaine HCl, 5 % HPBCD 6.07 5 % Lidocaine HCl, 10 % HPBCD 5.77 10 % Lidocaine HCl, 10 % HPBCD 5.70 10 % Lidocaine HCl, 20 % HPBCD 5.72 20 % Lidocaine HCl, 20 % HPBCD 5.50 20 % Lidocaine HCl, 40 % HPBCD 6.19Table 11 Articaine HCL formulations pH 2.5 % Articaine HCl, 2.5 % HPBCD 5.66 2.5 % Articaine HCl, 5 % HPBCD 6.13 5 % Articaine HCl, 5 % HPBCD 5.84 5 % Articaine HCl, 10 % HPBCD 5.74 10 % Articaine HCl, 10 % HPBCD 5.74 10 % Articaine HCl, 20 % HPBCD 5.80 20 % Articaine HCl, 20 % HPBCD 5.70 20 % Articaine HCl, 40 % HPBCD 6.14 Instruments and methods

[0199] HPLC Instrument: Waters ARC HPLC with a Waters 2998 PDA detector Column: Luna 5 μm C18(2) 100 Å 50 x 4.6 mm Guard Column: Phenomenex Security Guard AJ0-6071 Wavelength of analysis: 220 nm

[0200] The HPLC was run using a solvent system as set out in Table 12 below and included: Solvent A: 30 mM phosphate buffer (pH = 6.2), Solvent D: 70 % MeOH + 30 % 10 mM phosphate buffer. Table 12. Time Flow %A %D 1 Initial 1.00 67.0 33.0 2 9.00 1.00 5.0 95.0 3 11.00 1.00 5.0 95.0 4 11.25 1.00 67.0 33.05 12.50 1.00 67.0 33.0 6 12.75 0.00 67.0 33.0 Methods

[0201] Timed aliquots of the relevant formulations at 0, 25 and 60 ºC were taken at 4 days, 1 week, 2 weeks and 4 weeks.

[0202] Reaction rates double for every 10 ºC increase (~ x 16) therefore for the 60 ºC sample, 4 days = 9 weeks (2 months), 1 week = 16 weeks (4 months), 2 weeks = 32 weeks (8 months), and 4 weeks = 64 weeks (16 months). Results

[0203] The chromatograms, as exemplified by Figs 7a and 7b, across the formulations from the 2-week time point, displayed no changes when compared to time zero. Therefore, from the 60 ºC samples, even at the highest concentration, the formulations are stable up to16 months. Conclusion

[0204] The formulations demonstrate the suitability of the formulations for administration by subcutaneous injection as indicated. Example 6 Lidocaine and articaine formulations autoclave stability trial

[0205] Instruments and methods

[0206] HPLC Instrument: Waters ARC HPLC with a Waters 2998 PDA detector Column: Luna 5 μm C18(2) 100 Å 50 x 4.6 mm Guard Column: Phenomenex Security Guard AJ0-6071 Wavelength of analysis: 220 nm

[0207] The HPLC was run using a solvent system as set out in Table 13 below and included: ● Solvent A: 30 mM phosphate buffer (pH = 6-6.25), ● Solvent D = 75 % MeOH + 25 % 10 mM phosphate Table 13 Time Flow %A %D 1 Initial 1.00 67.0 33.0 2 9.00 1.00 5.0 95.0 3 11.00 1.00 5.0 95.0 4 11.25 1.00 67.0 33.0 5 12.50 1.00 67.0 33.0 6 12.75 0.00 67.0 33.0

[0208] Autoclaving was with an Iconclave (steam sterilizer) Instrument: Iconclave steam sterilizer STE-8-D Program: Liquid Temperature: 121 ºC (max temp = 124 ºC) Pressure: 110 kpa Holding time: 30 min Stability criteria

[0209] If there are no additional peaks in the chromatogram, the formulation is stable.

[0210] The Formulations comprised the compounds identified in Table 14 below: Table 14 Reagent Quantity CAS # Lidocaine HCl monohydrate 1590 mg 6108-05-0 Articaine HCl 750 mg 23964-57-0 2-Hydroxylpropyl-beta-cyclodextrin 1500 mg 128446-35-5 Sodium hydrogen carbonate (NaHCO3) 20 mg 144-55-8 Distilled H2O 100 mL 7732-18-5Method

[0211] Preparation of stock solutions Lidocaine HCl (150 mg / mL or 15 %) To a clean 10 mL volumetric flask on a balance was added 1590 mg of Lidocaine HCl monohydrate. Distilled water was added up to the mark and the flask was sonicated until all the powder dissolved. Articaine HCl (150 mg / mL or 15 %) To a clean 5 mL volumetric flask on a balance was added 1590 mg of Lidocaine HCl monohydrate. Distilled water was added up to the mark and the flask was sonicated until all the powder dissolved. 2-Hydroxylpropyl-beta-cyclodextrin (300 mg / mL or 30 %) To a clean 5 mL volumetric flask on a balance was added 1500 mg of 2-Hydroxylpropyl- beta-cyclodextrin. Distilled water was added up to the mark and the flask was sonicated until all the powder dissolved.

[0212] Preparation of sterile formulations (2 mL total) 1. In clean 3 mL vials, the following volumes of the relevant stock solutions were pipetted (table 15). 2. Where necessary, distilled water was added. 3. Using a calibrated pH meter, the pH of all the formulations was measured 4. 1 - 3 mg of NaHCO3 was added to each formulation where necessary to adjust to the final pH 5. The formulations were transferred to appropriate vials and crimped with a rubber lid and a foil lid. 6. The vials were transferred to the Iconoclave steam sterilizer and were sterilized at 121 ºC for 30 minutes using the liquid program Table 15a Formulation Lidocaine HPBCD Distilled Initial Final HCl (15%) (30 %) water pH pH 7.5 % Lidocaine 1 mL 0.5 mL 0.5 mL 5.38 6.28 HCl 7.5 % HPBCD7.5 % Lidocaine 1 mL 1 mL 0 mL 5.02 6.64 HCl 15 % HPBCD Table 15b Formulation Articaine HPBCD Distilled Initial Final HCl (400 (800 water pH pH mg / mL mg / mL) 7.5 % Articaine 1 mL 0.5 mL 0.5 mL 5.31 6.51 HCl 7.5 % HPBCD 7.5 % Articaine 1 mL 1 mL 0 mL 5.24 6.81 HCl 15 % HPBCD Results

[0213] The chromatograms are shown in Figs 8a-8d. Conclusions

[0214] Both Lidocaine HCL and Articaine HCl did not degrade under sterilization conditions at the pH stated. Example 7

[0215] Example 7 provides observational study data demonstrating the effectiveness of the use of lidocaine in the treatment of long COVID.

[0216] The lidocaine was provided at a concentration and using a mode of administration that targeted lymphatic delivery thereby enabling a therapeutic effective daily dose to be delivered to the patient.

[0217] The subcutaneous dose used ranged from 7mg / Kg to 14mg / Kg per day – split into 4 equal doses.

[0218] The formulation was a cyclodextrin inclusion complex in which the lidocaine was provided as a subcutaneous injection delivered at a lymphatic site, multiple times a day (four times daily). Each dose contained 125mg lidocaine with HPBCD where the ratio (by weight) of lidocaine to HPBCD was 1:3.

[0219] Details of the formulation are set out below: Formulation used in the study

[0220] Lidocaine HCl 5% and hydroxy propylated beta cyclodextrin HP-β-CD 15%, adjusted to pH 6.5 with sodium bicarbonate (NaHCO3). Methodology

[0221] In effect 2 outcomes were determined from the study. The primary outcome was from a health-related quality of life (HRQoL) assessment and secondary outcomes looked at symptomatic relief data obtained.

[0222] The study utilized an interrupted time series design over 24 weeks. Patients were screened for eligibility before the start of the treatment and began filling out a daily symptom severity questionnaire, establishing a pre-treatment period that averaged 27.7 ± 14.7 days.

[0223] The treatment consisted of lidocaine HCl 5% and beta cyclodextrin HP-β-CD 15%, adjusted to pH 6.5 with sodium bicarbonate (NaHCO3).

[0224] The administration schedule was as follows:

[0225] Weeks 1-7, 5ml Lidocaine-HP-β-CD (lidocaine 2.5%, HPBCD 7.5%) was administered subcutaneously bi-daily, delivering 7 mg / kg of lidocaine every other day, with a maximum of 500 mg lidocaine per day.

[0226] From weeks 7-14, the treatment was administered daily using 2.5ml lidocaine 5% and HPBCD 15%.

[0227] After 14 weeks, patients received a personalized treatment, with physicians adjusting medication dosages based on individual responses and ongoing symptoms. For non-responders, dosages were increased by 50% after 14 weeks, and further increased by another 50%, if necessary, up to 14 mg / kg / day, with a maximum of 1000 mg lidocaine per day. A guideline was in place for cases of prolonged non-response, advising discontinuation if patients showed no improvement and lost motivation.

[0228] The primary outcome was assessed using a health-related quality of life (HRQoL) assessment made using a Short Form 12 (version SF-12v2Dutch) questionnaire.

[0229] The SF-12 questionnaire (Table 16a) was assessed bi-weekly from week 0 to 24. Every 7 weeks, patients scored their satisfaction with the treatment and reported their Global Perceived Effect (version GPE-DV). The scoring is illustrated in Table 16b. Table 16a Order Question number (1-12) Category Response Options type 1 The following question is about your perspective on your health. This information helps track how you feel and how well you are able to carry out your usual activities. header 2 Poor (5), Moderate (4), Good (3), 1.How would you generally Very Good (2), describe your health? GH scores Excellent (1) 3 The following questions are about activities you may do on an average day. Are you currently limited by your health in these activities? If yes, to what extent? headerYes, severely limited (1), Yes, slightly limited (2), 2.Moderate exertion, such as moving a table, vacuuming, No, not swimming, or cycling. PF scores limited at all (3) Yes, severely limited (1), Yes, slightly limited (2), No, not limited 3.Climbing a few stairs. PF scores at all (3) How often in the past 4 weeks have you had any of the following problems with your work or other daily activities due to your physical health? header Always (1), Usually (2), Sometimes (3), 4.Have you achieved less than Rarely (4), you would like? RP scores Never (5) Always (1), Usually (2), 5.Were you limited in the kind Sometimes (3), of work or activities you could Rarely (4), do? RP scores Never (5)How often in the past 4 weeks have you experienced any of the following problems with your work or other daily activities due to emotional issues (such as depressive or anxious feelings)? header Always (1), Usually (2), Sometimes (3), 6.Have you achieved less than Rarely (4), you would like? RE scores Never (5) Always (1), Usually (2), 7.Did you do your work or other Sometimes (3), activities less carefully than Rarely (4), usual? RE scores Never (5) Very much (5), 8.To what extent have you been A lot (4), hindered by pain in your Quite a bit (3), normal work (both work outside the home and A little bit (2), household work) in the past 4 weeks? BP scores Not at all (1) These questions are about how you felt and how you were doing in the past 4 weeks. Please respond with the answer that best describes how you felt. How often in the past 4 weeks… headerAlways (1), Usually (2), Sometimes (3), 9.Did you feel calm and Rarely (4), satisfied? MH scores Never (5) Always (1), Usually (2), Sometimes (3), 10.Did you have a lot of Rarely (4), energy?VTscores Never (5) Always (1), Usually (2), Sometimes (3), 11.Did you feel downhearted Rarely (4), and depressed? MH scores Never (5) 12.How often have your physical health or emotional Always (1), problems hindered you in Usually (2), social activities (such as Sometimes (3), visiting friends or family, etc.) Rarely (4), in the past 4 weeks? SF scores Never (5)Table 16b

[0230] For the SF 12 a “normal” score would be 50, with a differential of 10 constituting a standard deviation. Thus, any results below 40 or above 60 constitute significant differences.

[0231] Additionally, changes in symptom severity were assessed daily from the pre- treatment period until week 24 using a questionnaire via a mobile application developed by ECC.

[0232] The questionnaire is provided in Table 17. Table 17 Order Symptom Response type 1 Fatigue rating 2 Endurance / exercise tolerance rating Symptoms of illness after exertion 3 (Post-exertional malaise (PEM)) rating Sensitivity to stimuli 4 (Sound, light, crowds) ratingShortness of breath and / or difficulty breathing rating Palpitations (Postural orthostatic tachycardia syndrome (POTS)) rating Dizziness rating Dizziness upon standing up or sitting rating Concentration problems rating Memory problems rating Sleep problems rating Pain complaints yes_no Pain in the face rating Sore throat rating Chest pain rating Joint pain rating Headache rating Muscle pain rating Pain in the lungs rating Problems with smell or taste rating Tinnitus rating Vision problems rating Skin abnormalities rating Anxiety feelings / feelings of depression rating24 Weakness / loss of muscle strength rating 25 Changes in the menstrual cycle rating 26 Chills / feeling of fever rating 27 Decreased daily functioning and / or mobility rating Other complaints yes_no 28 Hair loss rating 29 Nausea / vomiting rating 30 Diarrhoea rating

[0233] After treatment initiation, blood samples were taken to determine lidocaine plasma concentrations in the first eight patients.

[0234] Physicians evaluated the overall physical and psychological condition of patients every 7 weeks during follow-up appointments, documenting their clinical impressions in an Electronic Patient Dossier (EPD). Adverse events were monitored throughout the study.

[0235] Data, including patient-generated data from wearable devices, (Oura ring and Kubios HrV) was securely stored in a database (MySQL hosted on AWS, encrypted using AWS KMS with AES-256 encryption). A dedicated mobile application developed by ECC facilitated daily symptom assessments and communication with the clinical team, enhancing patient engagement and data collection. Outcomes

[0236] The primary outcome measure was a change in Health-related Quality of Life (HRQoL) at week 24 in the 103 participants diagnosed with post COVID, assessed using the 12-item Short-Form Health Survey (SF-12) (Tables 16a and 16b).

[0237] The results were viewed in two parts: ● Physical Component Summary (PCS) and ● Mental Component Summary (MCS).

[0238] The secondary outcomes included changes in 30 post COVID symptoms assessed by daily questionnaires (Table 17) and patient-perceived recovery measuredusing the Global Perceived Effect (GPE) scale in all 103 enrolled participants. The Global Perceived Effect (GPE) scale is a single-item measure used to assess how much a patient's condition has improved or worsened since a specific time point, commonly used in chronic pain research and clinical practice. Results

[0239] The primary analysis was conducted on these 103 patients.

[0240] Overall, 17% (18 of 103) of patients discontinued treatment before week 24.

[0241] The cohort consisted of 69 (67%) females and 34 (33%) males. The mean (SD) age of the participants was 48.1 (13.0) years, with a median (IQR) BMI of 25.8 kg / m² (23.0-29.1).96 of 103 participants (93.2%) were vaccinated against COVID-19. The median (IQR) duration of post COVID symptoms before treatment initiation was 31.5 months (24.28-43.27).

[0242] The primary outcome HRQoL estimated from a linear mixed model, was derived from a starting point or pre-treatment score for: ● MCS of 31.65, and ● PCS of 29.45.

[0243] The changes over the course of the study are provided in Table 18 below, with Fig 11 showing the data graphically. Table 18 Estimated PCS and MCS values on biweekly intervals Difference p-value 95% CI Cohen’s D PCS Week 2 0·63 0·47 -1·08 - 2·35 0·08 Week 4 0·43 0·57 -1·05 - 1·91 0·05 Week 6 1·08 0·09 -0·17 - 2·32 0·11Week 8 1·62 0·01 0·41 - 2·82 0·19 Week 10 1·98 <0·01 0·79 - 3·17 0·22 Week 12 1·96 <0·01 0·77 - 3·15 0·19 Week 14 1·14 0·07 -0·08 - 2·35 0·11 Week 16 1·75 0·01 0·52 - 2·98 0·17 Week 18 2·26 <0·01 1·00 - 3·51 0·23 Week 20 2·32 <0·01 0·87 - 3·77 0·21 Week 22 2·70 <0·01 1·25 - 4·16 0·25 Week 24 3·21 <0·01 1·71 - 4·71 0·31 MCS Week 2 1·34 0·19 -0·67 - 3·35 0·16 Week 4 3·10 <0·01 1·37 - 4·84 0·33 Week 6 4·12 <0·01 2·66 - 5·58 0·47 Week 8 3·74 <0·01 2·32 - 5·15 0·44 Week 10 4·03 <0·01 2·63 - 5·43 0·49 Week 12 5·59 <0·01 4·20 - 6·99 0·61 Week 14 6·31 <0·01 4·88 - 7·73 0·73 Week 16 6·11 <0·01 4·67 - 7·56 0·69 Week 18 6·42 <0·01 4·95 - 7·89 0·66 Week 20 6·07 <0·01 4·36 - 7·77 0·68 Week 22 5·02 <0·01 3·31 - 6·72 0·54Week 24 4·39 <0·01 2·64 - 6·15 0·44 Time points with p-values less than 0·05 are considered statistically significant. Cohen’D values of over 0.2 are considered significant, with a value of over 0.5 determining a moderate effect and above 0.8 a large effect. Statistical analysis was conducted using linear mixed-effect models.

[0244] During the lidocaine treatment, PCS demonstrated a gradual upward trajectory, with statistically significant improvements first emerging at week 8 (1·62 points, 95% CI: 0·41-2·82, p=0·009).

[0245] The MCS demonstrated a gradual upward trajectory, with statistically significant improvements first emerging at week 4 (3.10 points, CI: 1.37 - 4.84). The MCS showed continued improvement, reaching its peak at week 18 (6.42 points, 95% CI: 4.95- 7.89, p<0.001) , followed by a plateau phase through week 20 (6.07 points, 95% CI: 4.36- 7.77, p<0.001).

[0246] At 24 weeks of treatment, both the MCS and PCS score showed significant improvements.

[0247] The MCS increased by 4.39 points (95% CI: 2.64 - 6.15, p<0.001, Cohens’ d of 0.44).

[0248] The PCS rose by 3.21 points (95% CI: 1.71 - 4.71, p<0.001, Cohen’s d of 0.31).

[0249] These primary outcome measures, which are statistically significant, may be considered an indication of an effective treatment of Long COVID (separate of symptomatic relief as indicated by the secondary measures – see below).

[0250] For secondary outcomes, the patient symptom burden was monitored daily from an averaged 4 weeks pre-treatment through 24 weeks of treatment. All 103 enrolled participants were included in the analysis.

[0251] The results are shown in Table 19 below.Table 19 Difference p-value 95% CI Cohen’s D 1 Fatigue -0·671 <0·0001 -0·71 - - -0·41 0·63 2 Endurance / Exercise -0·72 <0·0001 -0·77 - -0·68 -0·45 tolerance 3 Post-exertional -1·07 <0·0001 -1·12 - -1·02 -0·53 malaise (PEM) 4 Hypersensitivity to -0·78 <0·0001 -0·83 - -0·74 -0·43 sensory input 5 Dyspnea -0·86 <0·0001 -0·90 - -0·81 -0·43 6 Heart palpitations -0·50 <0·0001 -0·54 - -0·47 -0·28 7 Dizziness -0·56 <0·0001 -0·60 - -0·52 -0·30 8 Orthostatic -0·76 <0·0001 -0·80 - -0·72 -0·40 dizziness 9 Concentration -0·67 <0·0001 -0·71 - -0·63 -0·41 problems 10 Memory loss -0·70 <0·0001 -0·75 - -0·66 -0·40 11 Sleep disturbances -0·56 <0·0001 -0·60 - -0·51 -0·27 12 Facial pain -0·23 <0·0001 -0·27 - -0·19 -0·16 13 Pharyngalgia -0·16 <0·0001 -0·22 - -0·11 -0·11 14 Chest pain -0·31 <0·0001 -0·35 - -0·26 -0·19 15 Joint pain -0·52 <0·0001 -0·58 - -0·47 -0·24 16 Cephalalgia -0·46 <0·0001 -0·53 - -0·40 -0·23 17 Muscle pain -0·73 <0·0001 -0·79 - -0·67 -0·36 18 Pleuratic pain -0·17 <0·0001 -0·22 - -0·13 -0·1019 Anosmia / -0·29 <0·0001 -0·31 - -0·26 -0·14 Ageusia 20 Tinnitus -0·16 <0·0001 -0·19 - -0·13 -0·07 21 Ocular problems -0·40 <0·0001 -0·43 - -0·37 -0·21 22 Skin abnormalities -0·31 <0·0001 -0·34 - -0·27 -0·18 23 Feelings of -0·48 <0·0001 -0·52 - -0·44 -0·22 anxiety / depression 24 Muscle weakness -0·63 <0·0001 -0·67 - -0·59 -0·32 25 Changes in the -0·12 <0·0001 -0·15 - -0·09 -0·09 menstrual cycle 26 Feverish feeling -0·33 <0·0001 -0·37 - -0·29 -0·19 27 Reduction in daily -0·84 <0·0001 -0·88 - -0·80 -0·51 functioning and / or mobility 28 Hair loss -0·05 0·07 -0·11- 0·00 -0·03 29 Nausea / Vomiting -0·31 <0·0001 -0·40 - -0·23 -0·19 30 Diarrhea -0·16 <0·0001 -0·27 - -0·06 -0·09 Estimated differences in symptom scores between pre-treatment phase and whole treatment duration.

[0252] Statistical analysis was conducted using linear mixed-effect models. Difference reflects the estimated change in symptom scores due to the treatment. P<0·05 is considered significant.

[0253] The 8 most debilitating symptoms with the highest pre-treatment burden were: ● Decreased daily functioning and / or mobility (5.566), ● Fatigue (5.530), ● Endurance / exercise tolerance (5.388), ● Symptoms of illness after exertion (PEM) (5.219), ● Sensitivity to stimuli (sound, light, crowds) (4.775),● Concentration problems (4,709), ● Weakness / loss of muscle strength, and (4.588) ● Muscle pain (4,556),

[0254] The data is shown graphically in Fig 9.

[0255] In contrast to the positive change shown over time with treatment, no signs of spontaneous improvements were observed in any of these measured symptoms during the pre-treatment period.

[0256] From the start of treatment, a gradual downward trend in symptom burden occurred until week 5 of treatment. At week 5 the symptomatic improvement was as follows: ● Decreased daily functioning and / or mobility (-0.784, CI: -.885 - -.683), ● Fatigue (-0.469, CI: -.571 - -.367), ● Endurance / exercise tolerance (-0.643, CI: -.742 - -.544), ● Symptoms of illness after exertion (PEM) (-1.033, CI: -1.154 - -.912), ● Concentration problems (-.354, CI: -.455 - -.253), ● Sensitivity to stimuli (sound, light, crowds) (-0.661, CI: -.772 - -.550), ● Muscle pain (-0.823, CI: -.971 - -.694), and ● Weakness / loss of muscle strength, and (-0.592, CI: -0.690 - -.494).

[0257] From week 5 to 7, a plateau in the effects occurred, where upon it was decided to treat the patients on a daily basis, as opposed to every other day. Upon this change in treatment, the gradual downward trend continued until week 24.

[0258] At 24 weeks of treatment, highly statistically treatment effects (p < 0.0001), were observed compared to the pre-treatment period as follows: ● Decreased daily functioning and / or mobility (-1.426, CI: -1.554 - -1.299), ● Fatigue (-1.159, CI: -1.288 - -1.031), ● Endurance / exercise tolerance (-1.261, CI: -1.386 - -1.137), ● Symptoms of illness after exertion (PEM) (-1.785, CI: -1.937 - -1.632), ● Concentration problems (-1.201, CI: -1.328 - -1.074), ● Sensitivity to stimuli (sound, light, crowds) (-1.258, CI: -1.398 - -1.118), ● Muscle pain (-1.146, CI: -1.327 - -.966), and ● Weakness / loss of muscle strength, and (-0.964, CI: -1.088 - -.841).

[0259] Furthermore, analysis of all 30 symptom scores demonstrated a significant decrease comparing the pre-treatment period with the whole treatment duration across all measured symptoms (p<0.0001), except hair loss (p=0.066), as outlined in Table 19 andrepresented graphically in Fig 10. Tables 17 and 19 have their symptoms numbered 1-30 due to some linguistic differences so as to ensure consistency with Fig 10.

[0260] The fact that the treatment showed a highly statistically significant effect across all symptom groups is astounding and is a strong indicator that the lidocaine is treating the underlying chronic, persistent or hyperinflammation and extends beyond Long COVID to other chronic, persistent or hyperinflammatory and autoimmune diseases as “grouped” in the background section of this specification and identified in Appendix 1. It also indicates that other formulations and dosage forms which target the lymph system, and which can administer an effective (and sustained) dosage resulting in predicted peak lymph level above 47µg / ml yet ensure plasma levels remain below the maximum tolerable plasma concentration of 4.7 µg / ml (0.02mM) will prove effective treatments for other related indications. Conclusion

[0261] This study assessed the effectiveness of lymph targeted lidocaine (formulated as a-HP-β-CD inclusion complex and delivered subcutaneously) on Long COVID patients.

[0262] The primary endpoint, indicative of effective treatment, was a statistically significant improvement in quality of life.

[0263] The findings revealed significant improvements in quality-of-life measures in 78% of the patients with Long COVID. These patients achieved a clinically significant reduction in symptom severity, characterized by substantial improvements in SF-12 domain scores (both physical and mental as characterised by an improvement in PCS and MCS) compared to pre-treatment levels. These changes were deemed clinically meaningful based on the magnitude of improvement and the impact on patients' overall well-being.

[0264] A small decline in Mental Component Summary (MCS) scores was observed in the final weeks of the study, which coincided with the transition into the winter months. This timing suggests that seasonal factors may have influenced mental well-being scores, as decreased daylight hours and weather changes during winter are known to impact mental health measures (Wyse et al., 2021)

[0265] Whilst the study design does not preclude the possibility of placebo effects. the effect size observed, with sustained improvement in 78% of patients, surpasses typical placebo effect rates in post COVID intervention studies [Enck, P., & Klosterhalfen, S. (2019). Placebos and the placebo effect in drug trials. In Handbook of Experimental Pharmacology (Vol.260, pp.399–431). Springer. https: / / doi.org / 10.1007 / 164_2019_2692]

[0266] Furthermore, the increased clinical improvement following a transition from alternate-day to daily administration over a seven-week period supports a dose-dependent effect, a pattern not typically associated with placebo effects.

[0267] Also, the delayed onset of improvements, typically occurring from 3 days to 3 weeks after treatment initiation in 80% is also indicative that it is a drug effect that is being seen.

[0268] A major strength of this study is the integration of extensive real-world data from a well-defined clinical cohort, with systematic repeated data collection via a standardized mobile application. The consistency of improvement across multiple domains including respiratory, autonomic, and neurocognitive symptoms suggests a broad- spectrum immunomodulatory effect.

[0269] The ability for patients to self-administer the treatment at home could potentially alleviate the strain on healthcare systems and improve access to care for the growing population of post COVID sufferers.

[0270] Another methodological strength of this study was the implementation of pre-treatment monitoring, which offered valuable insights into patients' pre-treatment conditions and strengthened the overall robustness of the study design. This pre-treatment period effectively established a baseline, enabling an interrupted-time-series study design. By allowing each patient to serve as their own control, the approach minimized variability from external factors and reduced potential confounding influences, thereby strengthening the reliability of pre- and post-treatment comparisons.Appendix 1 Diseases involving hyperinflammation – involving the activation of P2X7R of the immune system 1. Autoimmune diseases and immune-related diseases 2. Treatment-induced immune-related diseases 3. Infectious diseases 4. Cardiovascular diseases and neurovascular diseases 5. Neuroinflammatory and neurodegenerative diseases 6. Epileptic disorders 7. Affective disorders and psychiatric syndromes 8. Fibrosis 9. Cancer-related disorders 10. Cancer and neoplasms 11. Trauma and posttraumatic syndromes 12. Post-organ transplantation syndromes including transplanted organ rejection. 1. Autoimmune diseases and immune-related diseases Primary immunodeficiency Systemic inflammatory diseases: (1) Systemic syndrome in advance cancers (SIRS), (2) Sepsis: a. Bacterial sepsis: Pseudomonas spp., Staphylococcus spp., Streptococcus spp., b. Viral sepsis and ARDS: Influenza A virus, SARS, MERS, COVID-19, etc., c. Overwhelming post-splenectomy sepsis: Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, d. Babesiosis: Babesia microti (U.S.), B. divergens (Europe), e. Meningococcemia with sepsis and meningitis: N. meningitides, f. Rocky Mountain spotted fever (RMSF): Rickettsia rickettsia, g. Purpura fulminans: S. pneumoniae, H. influenzae, N. Meningitidis, h. Erythroderma, toxic shock syndrome: Group A Streptococcus, Staphylococcus aureus, i. Necrotizing fasciitis: Group A Streptococcus, mixed aerobic / anaerobic flora, Community- Associated Methicillin-Resistant Staphylococcus Aureus (CA-MRSA), j. Clostridial myonecrosis: Clostridium perfringens, k. Gas gangrene, (3) Hyperinflammation and cytokine storm, (4) Anaphylactic reaction including shock, (5) Systemic allergic reactions, (6) Systemic reactions (SIRS) following trauma, (7) Acute post-operative (post- transplantation) inflammation and SIRS. Endocrine diseases:(1) Type I and type II diabetes (2) Addison’s disease (3) Autoimmune polyendocrine syndrome (APS) type 1, 2 and 3 (4) Autoimmune pancreatitis (AIP), (5) Autoimmune thyroiditis (6) Ord's thyroiditis (7) Grave’s disease, (8) Hashimoto's disease, (9) Autoimmune oophoritis, (10) Endometriosis (11) Autoimmune orchitis, (12) Sjögren's syndrome, (13) Osteoporosis (14) Paget’s disease. Connective tissue diseases: (1) Mixed connective tissue disease, (2) Undifferentiated connective tissue disease (3) Adiposis dolorosa (4) Systemic lupus erythematosus (SLE), (5) Drug-induced lupus, (6) Adult-onset Still's disease, (7) CREST syndrome, (8) Enteritis-related arthritis, (9) Eosinophilic fasciitis, (10) Felty syndrome, (11) IgG4-related disease (12) Parry-Romberg syndrome, (13) Parsonage-Turner syndrome, (14) Sarcoidosis (15) Schnitzler syndrome, (16) Undifferentiated connective tissue disease (UCTD). Eye diseases: (1) Diabetic retinopathy, (2) Autoimmune retinopathy, (3) Autoimmune uveitis, (4) Intermediate uveitis, (5) Dry and wet Age-related Macular Degeneration (AMD), (6) Retinitis Pigmentosa (RP), (7) Ligneous conjunctivitis, (8) Mooren's ulcer, (9) Scleritis, (10) Sympathetic ophthalmia. Ear diseases (1) Autoimmune inner ear disease (AIED). Pulmonary diseases: (1) Asthma, (2) Allergic rhinitis (3) Chronic obstructive pulmonary disease (COPD), Gastrointestinal diseases: (1) Drug-induced liver diseases (2) Autoimmune hepatitis, (3) Inflammatory bowel syndrome, (4) Crohn's disease, (5) Ulcerative colitis (6) Irritable bowel syndrome, (7) Microscopic colitis, (8) Autoimmune enteropathy, (9) Coeliac disease, (10) Gluten intolerance, (11) Lactose intolerance, (12) Plummer-Vinson syndrome, (13); Achalasia, (14) Idiopathic peritonitis. Diseases of muscles, bone and skin: (1) Skin immune response following insect bites and stings (2) Contact dermatitis, (3) Polymyositis (4) Myositis, (5) Dermatomyositis, (6) Dermatitis of different causes, (7) Inclusion body myositis, (8) Fibromyalgia, (9) Systemic scleroderma, (10) Psoriasis, (11) Alopecia areata,(12) Autoimmune angioedema, (13) Autoimmune progesterone dermatitis (14) Autoimmune urticarial, (15) Bullous pemphigoid, (16) Cicatricial pemphigoid, (17) Gestational pemphigoid, (18) Dermatitis herpetiformis, (19) Discoid lupus erythematosus (20) Epidermolysis bullosa acquisita, (21) Erythema nodosum, (22) Hidradenitis suppurativa, (23) Lichen planus, (24) Lichen sclerosus, (25) Linear IgA disease (LAD), (26) Morphea (27) Pemphigus vulgaris (28) Pityriasis: a. Pityriasis alba,b. Pityriasis lichenoides chronica, c. Pityriasis rosea, d. Pityriasis circinata, e. Pityriasis rubra pilaris, f. Pityriasis versicolor, g. Dandruff, historically called Pityriasis capitis, h. Pityriasis amiantacea, i. Pityriasis lichenoides et varioliformis acuta (PLEVA), j. Mucha- Habermann disease, (29) Vitiligo, (30) Angioedema: a. Acquired angioedema, b. Hereditary angioedema, c. Antineurotic oedema (Quincke’s oedema), (31) Eczema, (32) Rheumatoid arthritis, (33) Chronic inflammation of the knee joints, hip joints, spine joints, etc., (34) Chronic spondylarthrosis, (35) Chronic osteochondritis and osteoarthritis (36) Juvenile arthritis, (37) Ankylosing spondylitis, (38) Psoriatic arthritis, (39) Palindromic rheumatism, (40) Relapsing polychondritis, (41) Polymyalgia rheumatica, (42) Antisynthetase syndrome. Urogenital diseases (1) Chronic interstitial cystitis (2) Recurrent cystitis, (3) Drug-induced nephropathies, (4) Diabetic nephropathy, (5) Nephrotic syndrome, (6) The nephritic syndrome, (7) Rapidly progressive glomerulonephritis, (8) Acute renal failure, (9) Secondary renal dysfunction. . Treatment-induced immune-related diseases (1) Radiation-induced encephalopathy, (2) Chemotherapy-related kidney injury: a. Complex renal cysts, b. Interstitial nephritis, c. Renal papillary necrosis, d. Renal infarction, e. Acute tubular necrosis (3) Chemotherapy-related bladder injury: a. Chemotherapy- induced cystitis, b. Haemorrhagic cystitis, (4) Chemotherapy-related gastrointestinal injury: a. Stomatitis, b. Pharyngitis, c. Oesophagopharyngitis, d. Mucositis, e. Oral and anal inflammation or ulceration, f. Bowel necrosis, g. Gastrointestinal ulceration, h. Enteritis, i. Pancreatitis, j. Acute hepatitis. . Infectious diseases Viral disease: Hepatitis A, B, C and D (HAV, HBV, HCV and HDV); Human retroviruses; Human immunodeficiency virus (HIV); HTLV-1; Abelson murine leukaemia virus; Rous sarcoma virus; Zika virus (ZiKV); Influenza A and B virus (IAV and IBV); Coronaviruses: MERS, SARS, SARS-CoV-2; Rhinoviruses; Human respiratory syncytial virus; Adenoviruses; Enteroviruses; Human metapneumoviruses; Herpes simplex or zoster encephalitis; Herpes simplex or zoster dermatitis; Herpesvirus type 6, 7 and 8; Dengue virus; West Nile virus; Ebolavirus and Marburgvirus Infections; Hendra virus; Nipa virus; Human papilloma virus (HPV); Epstein-Barr virus (EBV), Infectious mononucleosis; Rubeola: Measles virus; Rubella; Mumps; Smallpox; Chickenpox; Yellow fever; Viral myocarditis; Viral haemorrhagic fever; Rabies; Hand-foot-and-mouth disease; Orf Parapoxvirus; Molluscumcontagiosum Scrub typhus; Norovirus; Cytomegalovirus (CMV);Condyloma acuminatum; Parvovirus; Arthropod-borne and rodent-borne virus infections. Bacterial infections: Cat-scratch disease; Tularemia; Donovanosis; Nocardiosis; Actinomycosis and Whipple’s Disease; Typhoid; Leptospirosis; Q fever; Brucellosis; Melioidosis; Echinococcal (hydatid) disease; Chronic osteomyelitis; Lyme disease (Borrelia burgdorferi); Tick-borne spotted fevers; Tuberculosis; Buruli ulcer: Mycobacterium ulcerans; Cutaneous tuberculosis: M. tuberculosis; Leprosy: M. leprae; Helicobacter pylori; Schistosomiasis; Histoplasmosis; Entamoeba histolytica; Giardiasis; Filariasis; Visceral larva migrans; Anthrax: Bacillus anthracis; Ulceroglandular tularemia; Francisella tularensis; Bubonic plague: Yersinia pestis; Chancroid: Haemophilus ducreyi; Primary syphilis: T. pallidum; Gonococcal Infections; Syphilis; Treponematoses; Mycoplasma pneumoniae infections; Chlamydial infections; C. trachomatis infections; Meningitis, cerebritis and brain abscess; Bacterial meningitis; Brain abscess, suppurative intracranial infections; Cerebral malaria: Plasmodium falciparum; Spinal epidural abscess; Japanese encephalitis; Erysipelas Cellulitis; Folliculitis; Myositis and myonecrosis; Tetanus; Legionella infections; Infective gastroenteritis; Pneumonia; Acute respiratory distress syndrome (ARDS); Lung abscess; Infective endocarditis. Fungal infections: Mycoses, Coccidioidomycosis; Histoplasmosis; Blastomycosis; Phaeohyphomycosis; Penicilliosis; Sporotrichosis; Paracoccidioidomycosis; Candidiasis; Aspergillosis; Cryptococcosis; Mucormycosis (zygomycosis); Scedosporiosis; Trichosporonosis; Fusariosis; Pneumocystosis. Protozoal infections: Entamoeba histolytica; Malaria: Plasmodium falciparum; Babesiosis; Leishmaniasis; Chagas disease and African trypanosomiasis; Toxoplasmosis; Trichomoniasis. Helmintic infections. . Cardiovascular diseases and neurovascular diseases Brain: (1) Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), (2) Ischaemic stroke, (3) Aneurysmal subarachnoid haemorrhage, (4) Cerebral ischaemia following subarachnoid haemorrhage, (5) Cerebral vasospasm; Atherosclerosis; Systemic arterial hypertension; Pulmonary hypertension; Deep venous thrombosis and pulmonary embolism; Heart: (1) Angina pectoris, (2) Myocardial ischaemia, (3) Myocardial infarction, (4) Myocardial stunning, Myocardial hibernation, (5) Post-ischaemic myocardial dysfunction, (6) Ischaemic cardiomyopathy, (7) Atrial and ventricular arrhythmia including atrial fibrillation, (8) Post-myocardial infarctionsyndrome, (9) Post-pericardiotomy syndrome, (10) Pericarditis, (11) Myocarditis, (12) Rheumatic fever, (13) Cardiac complication after brain damage: a. Stress cardiomyopathy, b. Broken heart syndrome, c. Cardiac dysfunction and arrhythmia after subarachnoid haemorrhage, d. Cardiac dysfunction and arrhythmia after traumatic brain injury. . Neuroinflammatory and neurodegenerative diseases Alzheimer's disease; Parkinson's disease; Huntington’s disease; Extrapyramidal symptoms: (1) Acute dystonic reactions, (2) Oculogyric crisis, (3) Akathisia, (4) Pseudo- parkinsonism, (5) Tardive dyskinesia, Sydenham's chorea; Acute disseminated encephalomyelitis (ADEM); Hashimoto's encephalopathy; Bickerstaff's encephalitis; Anti- N-Methyl-D-Aspartate (Anti-NMDA) Receptor Encephalitis; Spinocerebellar ataxias; Susac's syndrome; Tolosa-Hunt syndrome; Meniere’s disease; Multiple sclerosis; Idiopathic inflammatory demyelinating diseases; Transverse myelitis; Neuromyelitis optica (Devic’s disease); Optic neuritis; Balo concentric sclerosis; Acquired neuropathies: a. Chronic secondary polyneuropathies, b. Chronic inflammatory demyelinating polyneuropathy (CIDP), c. Progressive inflammatory neuropathy, d. Guillain Barré syndrome, e. Critical illness polyneuropathy, f. Acute and chronic motor axonal neuropathy; Hereditary neuropathies: a. Charcot-Marie-Tooth disease type 1, 2 and 3, b. Hereditary neuralgic amyotrophy; Myotonic dystrophy type I and II; Amyotrophic lateral sclerosis (ALS); Neuralgic amyotrophy (Parsonage-Turner Syndrome); Neuromyotonia; Myasthenia gravis; Restless legs syndrome; Stiff-person syndrome. . Epileptic disorders Generalised epileptic seizures (grand mal) including status epilepticus; Focal epileptic seizures: a. Frontal lobe epilepsy, b. Temporal lobe epilepsy, c. Benign Rolandic epilepsy, d. Benign occipital epilepsy of childhood; Autosomal dominant nocturnal frontal lobe epilepsy; Childhood absence epilepsy; Dravet syndrome; Epilepsy in females with mental retardation; Juvenile myoclonic epilepsy; Lennox-Gastaut syndrome; Febrile infection-related epilepsy syndrome; West syndrome; Ohtahara syndrome; Reflex epilepsies; Progressive myoclonic epilepsies; Rasmussen's encephalitis. . Affective disorders and psychiatric syndromes Schizophrenia; Depression; Bipolar disorder; Occupational burnout; Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS); Attention deficit hyperactivity disorder Posttraumatic stress disorder; Fibromyalgia.. Fibrosis Primary fibrosis: Interstitial pulmonary fibrosis (ILD); Retroperitoneal fibrosis; Primary biliary cholangitis (primary biliary cirrhosis or primary liver cirrhosis). Disease-induced fibrosis: Secondary pulmonary fibrosis; Secondary inflammation due to cystic fibrosis; Primary sclerosing cholangitis; Interstitial bladder fibrosis; Secondary liver cirrhosis: a. Alcoholic cirrhosis, b. Hepatitis C-induced cirrhosis, c. Human immunodeficiency virus-induced cirrhosis, d. Metastatic carcinomatosis cirrhosis. Cancer-induced fibrosis: Fibrosis formation induced by cancer. Tumour pseudoprogression: Treatment induced fibrosis mimicking tumour progression especially in neuroendocrine tumours. Treatment-induced fibrosis: Fibrosis formation induced by medical, surgical or radioactive treatments, i.e. Post abdominal operation peritoneal fibrosis with or without ileus; Fibrosis following organ transplantation; Chemotherapy-induced chronic gastrointestinal fibrosis. . Paraneoplastic syndromes: Paraneoplastic cerebellar degeneration; Lambert-Eaton myasthenic syndrome; Paraneoplastic cerebellar degeneration; Encephalomyelitis, limbic encephalitis; Brainstem encephalitis; Opsoclonus myoclonus ataxia syndrome; Anti-NMDA receptor encephalitis; Polymyositis; Acanthosis nigricans; Dermatomyositis; Leser-Trélat sign; Necrolytic migratory erythema; Sweet's syndrome; Florid cutaneous papillomatosis; Pyoderma gangrenosum; Acquired generalized hypertrichosis. 0. Cancer and neoplasms Immune-related and neoplastic blood diseases: Aplastic anaemia; Antiphospholipid syndrome (APS, APLS); Thrombotic thrombocytopenic purpura (TTP); Idiopathic thrombocytopenic purpura (ITP); Autoimmune haemolytic anaemia; Autoimmune lymphoproliferative syndrome; Autoimmune neutropenia; Cold agglutinin disease; Essential mixed cryoglobulinemia; Evans syndrome; Pernicious anaemia; Pure red cell aplasia; Thrombocytopenia; Lymphangitis carcinomatosis; Myelodysplastic / myeloproliferative neoplasms (MPN / MPD): (1) Polycythaemia vera, (2) Essential thrombocythemia, (3) Primary myelofibrosis, (4) Fibrotic myelofibrosis, (5) Lymphomas: a. Non-Hodgkin Lymphoma, b. Non-Hodgkin Lymphoma in Children (Burkitt lymphoma), c. Hodgkin Disease, d. Lymphoma of the skin, e. Waldenström macroglobulinemia, f. Multiple myeloma (Kahler’s disease), g. Primary cerebral lymphoma,(6) Leukaemia: a. Acute myeloid leukaemia, b. Chronic myeloid leukaemia, c. Acute lymphocytic leukaemia, d. Chronic lymphocytic leukaemia, (6) Unclassifiable MPN / MPD. Solid tumours: A. Neuroendocrine tumours (NETs) (1) Pituitary gland: NET of the anterior pituitary, (2) Thyroid gland: Neuroendocrine thyroid tumours and medullary carcinoma, (3) Parathyroid NETs, (4) Thymus and mediastinal carcinoid tumours, (5) Pulmonary NETs: a. Bronchial NETs, b. Pulmonary carcinoid tumours: typical carcinoid and atypical carcinoid, c. Small-cell lung cancer (SCLC), d. Large cell neuroendocrine carcinoma of the lung (LCNEC), e. Extrapulmonary small cell carcinomas (ESCC or EPSCC), (6) Gastroenteropancreatic neuroendocrine tumours (GEP-NET): a. Foregut NETs (stomach, proximal duodenum, thymus, lung and bronchus), b. Pancreatic NETs, c. Midgut GEP-NET (from distal half of 2nd part of the duodenum to the proximal two-thirds of the transverse colon), appendix NETs, e. Hindgut NETs, (7) Liver and gallbladder NETs, (8) Adrenal tumours and adrenomedullary tumours, (9) , (10) Pheochromocytoma, (11) Peripheral nervous system NETs: a. Schwannoma, b. Paraganglioma, c. Neuroblastoma, (12) Breast NETs, (13) Genitourinary tract NETs: a. urinary tract carcinoid tumour and neuroendocrine carcinoma, b. ovary NETs, c. NETs of the cervix, d. Prostate NETs, e. Testes NETs, (14) Merkel cell carcinoma of skin (trabecular cancer), (15) Hereditary NETs: a. Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2), b. Von Hippel-Lindau (VHL) disease, c. Neurofibromatosis type 1 and type 2, d. Schwanomatosis, e. Tuberous sclerosis, f. Carney complex (LAMB or NAME syndrome). B. Central nervous system tumours (1) Brain tumours and spinal tumours: a. Metastatic brain tumours, b, Pilocytic astrocytoma, c. Glioma, d. Glioblastoma multiforme (GBM), e. Oligodendroglioma, f. Ependymoma, g. Medulloblastoma, h. Meningeal tumours, i. Meningioma, j. Metastatic meningitis carcinomatosis. C. Oropharyngeal tumours: Benign tumours: Eosinophilic granuloma, Fibroma, Granular cell tumour, Keratoacanthoma, Leiomyoma, Osteochondroma, Lipoma, Schwannoma, Neurofibroma, Papilloma, Condyloma acuminatum, Verruciform xanthoma, Pyogenic granuloma, Rhabdomyoma, Odontogenic tumours, Precancerous lesions, Leukoplakia, Erythroplakia, Erythroleukoplakia, Malignant tumours, Squamous cell carcinoma, Verrucous carcinoma, Minor salivary gland carcinomas, Lymphomas. D. Laryngeal cancer Paranasal sinus and nasal cavity cancer, Nasopharynx cancer, Teratomas, Adenocarcinomas, Adenoid cystic carcinomas, Mucoepidermoid carcinomas, Salivary gland cancer, Thyroid cancers: a. Papillary thyroid cancer, b. Non-invasive follicular thyroidneoplasm with papillary-like nuclear features, c. Follicular thyroid cancer, c. Poorly differentiated thyroid cancer, d. Anaplastic thyroid cancer, e. Thyroid lymphoma, f. Squamous cell thyroid carcinoma, g. Sarcoma of thyroid, h. Hürthle cell carcinoma. E. Skin cancers Basal-cell carcinoma, squamous-cell carcinoma, Malignant melanoma, Kaposi sarcoma, F. Cancer of the vascular system Angiosarcomas, Epithelioid haemangioendotheliomas, Haemangiopericytomas, Lymphangiosarcomas, Kaposiform haemangioendotheliomas (KHEs), Infantile haemangioma, Congenital haemangioma, Haemangioblastoma, Pyogenic granuloma, Tufted angioma, Glomus tumour. G. Muscle and bone tumours Leiomyoma, Leiomyosarcoma, Smooth muscle tumour of uncertain malignant potential (STUMP), Metastatic tumours, Osteosarcoma, Chondrosarcoma, Ewing's sarcoma, Fibrosarcoma, Undifferentiated pleomorphic sarcoma, Teratomas, Osteoma, Osteoid osteoma, Osteochondroma, Osteoblastoma, Enchondroma, Giant cell tumour of bone, Aneurysmal bone cyst. H. Breast cancer Metastatic tumours, Invasive ductal carcinoma, Invasive lobular carcinoma, Tubular carcinoma, Mucinous (colloid) carcinoma, Carcinomas with medullary features, Invasive papillary carcinoma, Breast lymphoma, Breast sarcoma. I. Lung tumours Metastatic tumours, Bronchial leiomyoma, Primary lung cancers: a. Small-cell lung carcinoma (SCLC), b. Non-small-cell lung carcinoma NSCLC), c. Pleuropulmonary blastoma, d. Lymphomas of the lung, e. Sarcomas of the lung, f. Mediastinal tumours, g. Pleural tumours, h. Malignant mesothelioma, j. Pleural sarcomas, k. Pleural angiosarcoma, l. Pleural desmoplastic small round cell tumour (pleural DSRCT), m. Pleural synovial sarcoma, n. Pleural solitary fibrous tumour (pleural SFT), o. Smooth muscle tumours of the pleura, p. Pleural carcinomas, q. Pleural mucoepidermoid carcinoma, r. Pleural pseudomesotheliomatous adenocarcinoma, s. Pleural calcified fibrous pseudotumour. J. Gastrointestinal tumours (1) Krukenberg tumour (metastatic tumour): (2) Oesophageal cancer, a. Squamous-cell carcinoma (ESCC), b. Oesophageal adenocarcinoma (EAC), c. Barrett's oesophagus, d. Gastric cancer, e. Gastric adenocarcinoma, f. Signet ring cell carcinoma, g. Gastric lymphoma, h. Extranodal marginal zone B-cell lymphomas (MALT lymphoma), (2) Carcinoid: a. Duodenal adenocarcinoma, b. Appendix, c. Carcinoid (3) Pseudomyxoma peritonei: a. Colorectal tumours (4) Colorectal polyp: a. adenoma, b. hyperplastic, c. juvenile, d. sessile serrated adenoma, e. traditional serrated adenoma, f. Peutz-Jegherssyndrome,(5) Cronkhite-Canada syndrome, (6) Polyposis syndromes: a. Juvenile MUTYH- associated, familial adenomatous and serrated polyposis, (7) Adenocarcinoma, 8) Familial adenomatous polyposis, (10) Hereditary nonpolyposis colorectal cancer, (11) Anal tumour: Squamous cell carcinoma, (12) Liver cancer, (13) Metastatic tumours, (14) Hepatocellular carcinoma, (15) Hepatoblastoma, (16) Hepatocellular adenoma, (17) Cavernous haemangioma, (18) Focal nodular hyperplasia, (19) Nodular regenerative hyperplasia, (20) Gallbladder cancer, (21) Cholangiocarcinoma, (22) Klatskin tumour, (23) Gallbladder adenocarcinoma, (24) Pancreatic cancer, (25) Exocrine tumours: a. Adenocarcinoma, b. Pancreatic ductal adenocarcinoma, (26) Cystic neoplasms: a. Serous microcystic adenoma, b. Intraductal papillary mucinous neoplasm, c. Mucinous cystic neoplasm, d. Solid pseudopapillary neoplasm, e. Pancreablastoma, (27) Endocrine PanNETs: a. MALT lymphomas, b. Peritoneal tumours, (28) Metastatic peritonitis carcinomatosis. K. Urogenital cancers (1) Renal tumours: a. Metastatic tumour, b. Renal cell carcinoma (RCC): b1. Clear cell RCC, b2. Papillary RCC, b. Chromophobe RCC, b4. Collecting duct RCC, c. Clear cell sarcoma, d. Mesoblastic nephroma, e. Wilm’s tumour (nephroblastoma), f. Renal oncocytoma, g. Cystic nephroma, h. Angiomyolipoma, i. Metanephric adenoma, j. Renal medullary fibroma, (2) Ureteral cancer: a. Transitional cell carcinoma, b. Ureteral neoplasm, (3) Bladder tumours: a. Metastatic tumours, b. Papillary transitional cell carcinoma, c. Non-papillary transitional cell carcinoma, d. Squamous cell carcinoma, e. Adenocarcinomas, f. Sarcomas, g. Small cell carcinomas, (4) Ovarian tumours, a. Malignant ovarian cancer: a1. Epithelial cancers, a2. Germ cell cancers, a3. Stromal cancers, b. Benign: b1.Surface epithelial tumours, b2. Stromal tumours, b3. Germ cell tumours, (5) Uterine tumours: a. Uterine fibroids or leiomyomas (6) Cervical tumours: a. Cervical cancer, a1. Squamous cell carcinoma, a2. Adenocarcinoma, a3. Adenosquamous carcinoma, a4. Small cell carcinoma, a5. Neuroendocrine tumour, a6. Glassy cell carcinoma, a7. Villoglandular adenocarcinoma, b. Cervical intraepithelial neoplasia, (7) Testicular tumours: a. Germ cell tumours: a1. Intratubular germ cell neoplasia, a2. Seminoma, a3. Spermatocytic tumour, a4. Embryonal carcinoma, a5. Yolk sac tumour, b. Trophoblastic tumours: b1. Choriocarcinoma, b2. Monophasic choriocarcinoma, b3. Placental site trophoblastic tumour, b4. Cystic trophoblastic tumour, c. Teratomas: c1. Dermoid cyst, c2. Epidermoid cyst, c3. Monodermal teratoma (Carcinoid), c4. Primitive neuroectodermal tumour (PNET), c5. Nephroblastoma-like tumour, c6. Teratomic tumour with somatic-type malignancy, d. Sex cord - gonadal stromal tumours: d1. Leydig cell tumour, d2. Sertoli cell tumour, d3. Lipid rich variant, d4. Sclerosing variant, d5. Large cell calcifying variant, d6. Intratubular Sertoli cell neoplasia in Peutz-Jeghers syndrome, d7. Granulosa cell tumour, d8. Adult type, d9. Juvenile type, d10.Thecoma fibroma group, d11.Thecoma, d12. Fibroma, d13. Incompletely differentiated tumours, d14. Mixed types tumours, e. Mixed germ cell and sex cord / gonadal stromal tumours: e1. Gonadoblastoma, e2. Germ cell-sex cord / gonadal stromal tumour, unclassified, f. Miscellaneous tumours of the testis: f1. Lymphomas: f1a. Primary testicular diffuse large B-cell lymphoma, f1b. Mantle cell lymphoma of the testes, f1c. Extranodal marginal zone B cell lymphoma of the testes, f1d. Extranodal NK / T-cell lymphoma, nasal type of the testes, f1e. Peripheral T-cell lymphoma of the testes, f1f. Activin receptor-like kinase-1–negative anaplastic large cell lymphoma of the testes, f1g. Paediatric-type follicular lymphoma of the testes, f2. Carcinoid, f3. Tumours of ovarian epithelial types: f3a. Serous tumour of borderline malignancy, f3b. Serous carcinoma, f3c. Well differentiated endometrioid tumour, f3d. Mucinous cystadenoma, f3e. Mucinous cystadenocarcinoma, f3f. Brenner tumour, f4. Nephroblastoma. f5. Paraganglioma, g. Haematopoietic tumours, h. Tumours of collecting ducts and rete: h1. Adenoma, h2. Carcinoma, i. Tumours of the paratesticular structures: i1 Adenomatous tumour, i2.Malignant and benign mesothelioma, i3. Adenocarcinoma of the epididymis, i4. Papillary cystadenoma of the epididymis, i5. Melanotic neuroectodermal tumour, i6. Desmoplastic small round cell tumour, j. Mesenchymal tumours of the spermatic cord and testicular adnexae: j1. Lipoma. J2. Liposarcoma, j3. Rhabdomyosarcoma, j4. Aggressive angiomyxoma, j5. Angiomyofibroblastoma-like tumour (see myxoma), j6. Fibromatosis, j7. Fibroma, j8. Solitary fibrous tumour, j9. Others, k. Secondary tumours of the testis, (8) Urethral cancer: a. Transitional cell carcinoma, b. Squamous-cell carcinoma, c. Adenocarcinoma, d. Melanoma, e. Prostate tumours, f. Metastatic prostate tumour, g. Benign prostatic hyperplasia, i. Prostate cancer, (9) Penile tumours: a. Phimosis, b. Penile cancer. L. Retroperitoneal tumours (1) Solid tumours: a. Metastatic tumour, b. Fibroma, fibrosarcoma, malignant fibrous histiocytoma, c. Lipoma, liposarcoma, d. Leiomyoma, leiomyosarcoma, e. Desmoid tumours. e. Ganglioneuroma, ganglioneuroblastoma, f. Schwannoma, neurofibroma, g. Extragonadal germ cell tumour, h. Lymphoma, i. Lymphadenopathy, (2) Cystic tumours, a. Cystic lymphangioma, b. Cystic teratoma, c. Cystadenoma, cystadenocarcinoma, d. Cystic mesothelioma. e. Epidermoid cyst, f. Tarlov cyst (perineural cyst). 1.Trauma and posttraumatic syndromes (1) Traumatic subarachnoid haemorrhage, (2) Head injury including severe traumatic head injury, (3) Cerebral ischaemia following traumatic brain injury, (4) Polytrauma condition, (5) Posttraumatic epileptic seizures. 2. Inflammation after organ transplantation of lung, kidney, heart, liver, etc.(1) Acute immune reaction after organ transplantation, (2) Chronic organ tissue rejection reaction by the host, (3) Fibrosis following organ transplantation.

Claims

CLAIMS 1. An inclusion complex comprising: i) an active pharmaceutical ingredient (API) which is a P2X7 receptor antagonist; and ii) a cyclodextrin; for use in the treatment of an autoimmune disease or a condition in which an immune response caused by a disease or infection causes chronic, persistent or hyperinflammation, wherein the inclusion complex is presented for administration to the lymphoid system.

2. An inclusion complex as claimed in claim 1 wherein the autoimmune disease or the condition in which the immune response caused by the disease or infection causes chronic, persistent or hyperinflammation is a post viral condition.

3. An inclusion complex as claimed in claim 2 wherein the post viral condition is Long COVID.

4. An inclusion complex as claimed in any of the preceding claims wherein the inclusion complex is presented for administration by way of intradermal, subdermal or sub- cutaneous delivery.

5. An inclusion complex as claimed in claim 4 which is presented in a pen injector.

6. An inclusion complex as claimed in claim 5 wherein the pen injector comprises from 0.5 to 5.0 ml of a solution of the inclusion complex.

7. An inclusion complex as claimed in claim 6 wherein the pen injector comprises the solution of the inclusion complex at a concentration of at least 1%.

8. An inclusion complex as claimed in claim 4 which is presented in an infusion pump.

9. An inclusion complex as claimed in claim 8 wherein the infusion pump comprises from 5 ml to 1000 ml of a solution of the inclusion complex.

10. An inclusion complex as claimed in claim 9 wherein the infusion pump comprises the solution of the inclusion complex at a concentration of at least 0.5%.

11. An inclusion complex as claimed in any of the preceding claims wherein the API is Lidocaine or a salt thereof, or Articaine or a salt thereof.

12. An inclusion complex as claimed in claim 11 which is a base.

13. An inclusion complex as claimed in claim 11 which is a salt.

14. An inclusion complex as claimed in claim 13 which is a hydrochloride salt.

15. An inclusion complex as claimed in any of the preceding claims wherein the cyclodextrin is a β cyclodextrin.

16. An inclusion complex as claimed in claim 15 which is a hydroxy propylated (HP) β cyclodextrin.

17. An inclusion complex as claimed in any of the preceding claims further comprising a pH modifier.

18. An inclusion complex as claimed in claim 17 wherein the pH modifier is an alkali.

19. An inclusion complex as claimed in claim 18 wherein the pH modifier is sodium bicarbonate.

20. A formulation comprising an inclusion complex of: i) Lidocaine HCl or Articaine HCl; and ii) Hydroxy propylated β cyclodextrin (HPBCD);together with iii) a pH modifier; and iv) water wherein the pH is between 5 and 7.4, i) and ii) are present in a ratio of between 1:1 and 1:6; and the concentration of i) is between 2.5% and 20% weight / volume.

21. A formulation as claimed in claim 20 wherein: i) and ii) are present in a ratio of 1:1, 1:2 or 1:3 22. A formulation as claimed in claim 20 or 21 with a shelf life of at least 32 weeks based on accelerated stability testing at 60º C.

23. A formulation as claimed in claim 20, 21 or 22 which is presented for subcutaneous delivery.

24. A formulation as claimed in claim 23 which is presented as a small volume injectable with a volume of 5ml or less.

25. A formulation as claimed in claim 24 which is presented as a small volume injectable with a volume of 3ml or less.

26. A formulation as claimed in claim 23 which is presented for infusion by way of a pump over 1 to 30 days.

27. A formulation as claimed in any of claims 20 to 26 which is presented to deliver a unit dose of at least 0.5mg / kg of lidocaine or a salt thereof to a patient over a 24 hour period, which dose results in a predicted peak lymph level above 47µg / ml and a peak plasma level of below 4.7µg / ml for lidocaine.

28. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition wherein the lidocaine or a salt thereof is administered in a format and at a dose that targets the lymphatic system, resulting in predicted peak lymph level above 47µg / ml and a peak plasma level for lidocaine of below 4.7µg / ml.

29. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 28 wherein the treatment is a causal treatment.

30. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 29 wherein the causal treatment is indicated by an improvement in health-related quality of life (HRQoL). 31.. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 30 wherein the improvement in health- related quality of life (HRQoL) is physical, as indicated by a physical component score (PCS).

32. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 30 or 31 wherein the improvement in health-related quality of life (HRQOL) is mental, as indicated by a mental component score (MCS).

33. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 28 wherein the treatment is a symptomatic treatment.

34. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 33 wherein the symptomatic treatment is selected from one or more of: ● Cardiovascular functioning, symptoms and conditions; ● Fatigue or exhaustion; ● Pain; ● Nervous system functioning, symptoms and conditions;● Cognitive functioning, symptoms and conditions; ● Mental health functioning, symptoms and conditions; ● Respiratory functioning, symptoms and conditions; ● Post exertion symptoms; and ● Physical functional symptoms and conditions.

35. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 34 wherein the cardiovascular symptom is selected from one or more of: heart palpitations (POTS), orthostatic dizziness and chest pain.

36. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 34 wherein the Fatigue or exhaustion is selected from one or more of: fatigue and endurance / exercise tolerance.

37. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 34 wherein the pain is selected from one or more of: joint pain, muscle pain, pleuritic pain, cephalalgia, facial pain and pharyngalgia.

38. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 34 wherein the Nervous system symptom is selected from one or more of: dizziness, sleep disturbance, tinnitus, anosmia / ageusia, ocular problems, and hypersensitivity to sensory input.

39. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 34 wherein the Cognitive functioning symptom is selected from one or more of: memory loss and concentration problems.

40. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 34 wherein the Mental health symptom is a feeling of anxiety / depression.

41. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 34 wherein the Respiratory symptom is dyspnoea.

42. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 34 wherein the Post exertion symptom is post-exertional malaise (PEM).

43. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 32 wherein the Physical symptom is selected from one or more of: reduction in daily functioning / mobility, muscle weakness, diarrhoea, nausea / vomiting, feverish feeling, skin abnormalities, hair loss, and changes in menstrual cycle.

44. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in any of claims 28 to 43 where the hyperinflammatory condition is selected from: ● Autoimmune Diseases; ● Cardiovascular Diseases; ● Gastrointestinal Disorders: ● Lung Diseases; and ● Other diseases selected from o Cancers; o Alzheimer's Disease o Parkinson's Disease o Type 2 Diabetes o Depression and Anxiety; and o Fatty Liver Disease.

45. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 44 wherein the autoimmune disease is selected from: ● Post-Acute Infection Syndromes (PAISs);● Rheumatoid Arthritis; ● Lupus (Systemic Lupus Erythematosus); ● Psoriasis; ● Ankylosing Spondylitis; ● Multiple Sclerosis; and ● Type 1 Diabetes.

46. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 44 wherein the Cardiovascular disease is selected from heart disease or high blood pressure.

47. Lidocaine for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 44 wherein the gastrointestinal disease is selected from ● Irritable bowel disease; ● Crohn's disease; and ● Ulcerative colitis.

48. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 44 wherein the lung disease is selected from ● Asthma; and ● COPD.

49. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in any of claims 28 to 48 wherein the format that targets the lymphatic system is one of invasive or topical.

50. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 49 wherein the invasive administration is: ● Subcutaneous; ● Intradermal; or ● Subdermal.

51. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 49 wherein the topical administration is: ● Oral; ● Pulmonary; ● Transdermal; or ● Nasal.

52. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in claim 51 wherein the oral route is: ● Sub-lingual; ● Buccal; or ● Oropharyngeal.

53. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in any of the preceding claims wherein the daily dose is at least 0.5mg / Kg lidocaine.

54. Lidocaine or a salt thereof for use in the treatment of a chronic, persistent or hyperinflammatory condition as claimed in any of the preceding claims wherein the lidocaine or a salt thereof is formulated as an inclusion complex with HPBCD.

55. A method of treating a subject having a chronic, persistent or hyperinflammatory condition comprises administering an effective dose of Lidocaine or a salt thereof in a format and at a dose that targets the lymphatic system, resulting in predicted peak lymph level above 47µg / ml and a peak plasma level for lidocaine of below 4.7µg / ml.

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