Lidocaine or Articaine for Treating COVID-19, Autoimmune Disease, or Cytokine Storm Response

Abstract

The present invention relates to high dose / low volume formulations of lidocaine or its salts or articaine or its salts for use in the treatment of COVID-19 or autoimmune diseases or conditions where the immune response resulting from disease or infection causes a cytokine storm. More specifically, the present invention relates to the treatment of Long COVID and addresses the challenge of getting an effective dose of lidocaine or articaine into the plasma to treat systemic inflammation without causing toxicity.

Description

[Technical field]

[0001] The present invention relates to compositions and methods for treating autoimmune diseases or conditions in which treatment of an immune response resulting from disease or infection is required. Such immune responses lead to hyper-inflammation, including but not limited to cytokine storm, resulting in acute respiratory distress syndrome (ARDS) or cytokine storm syndrome (CSS), as may occur in SARS-CoV-2 disease (COVID-19). The present invention further relates to the treatment of systemic inflammation (including hyper-inflammation) and symptoms thereof following infection, such as occurs in Long COVID. [Background technology]

[0002]

[0002] The COVID-19 pandemic has led many groups to urgently examine the repurposing of approved drugs that can address the symptoms of COVID-19 and the long-term effects of infection.

[0003]

[0003] Acute respiratory distress syndrome (ARDS) is the main cause of morbidity and mortality in coronavirus disease 19 (COVID-19), for which there is currently no effective treatment other than respiratory support and the use of high-dose dexamethasone.

[0004]

[0004] Many drugs, such as chloroquine and ivermectin, have been studied in hospitalized patients with severe symptoms of SARS-CoV-2 infection, but none have been successful.

[0005]

[0005] ARDS is caused by and maintained by uncontrolled inflammatory activation characterized by massive release of cytokines (cytokine storm), diffuse pulmonary edema, inflammatory cell infiltration, and disseminated coagulation. Dysfunction of macrophages and T lymphocytes plays a central role in this syndrome.

[0006]

[0006] In several experimental in vitro and in vivo models, many of these pathophysiological changes are triggered by stimulation of the P2X7 receptor.

[0007] In this regard, viral pathogens in the airways induce cellular stress and subsequent innate immune responses. This leads to massive ATP exocytosis, resulting in high extracellular ATP concentrations. Initially, ATP stimulates the purinergic P2Y2 and P2X4 receptors, resulting in a short period of surfactant exocytosis, but as ATP levels continue to rise, the P2X4 and P2Y2 receptors become insensitive, preventing normal release of surfactant. When extracellular ATP levels begin to exceed a low threshold for activation of the P2X7 extracellular ATP receptor (P2X7R), located on the cell surface of innate immune cells, it triggers a proinflammatory response of innate immunity, followed by a massive release of inflammatory mediators and a subsequent cytokine storm. The resulting vascular leakage and pulmonary edema induce the degradation and inactivation of pulmonary surfactant, a key factor in the pathogenesis of ARDS, leading to alveolar collapse and reduced gas exchange.

[0008]

[0008] The applicant hypothesized that this P2X7 receptor may be an ideal candidate to target in COVID-19-associated ARDS and long COVID. Unfortunately, most of the known P2X7 receptor blockers are toxic when given to patients at the dose levels required for effective treatment.

[0009]

[0009] The applicant hypothesized that autoimmune diseases could be treated in the same way, i.e., by blocking the P2X7 receptor with an effective dose of a similar drug such as lidocaine or articaine. Articaine contains a thiophene ring rather than a benzene ring, which has the advantage of increasing lipid solubility and therefore diffusion, resulting in higher efficacy (x1.5) and lower toxicity (0.6).

[0010]

[0010] The prior art identified includes:

[0011] Trials, Volume 22, Issue 1, 2021, Muller Marie et al., “impact of intravenous lidocaine on clinical outcomes of patients with ARDS during COVID-19 pandemia (LidoCOVID): A structured summary of a study protocol for a randomized control trial,” p. 131;

[0012] Bone Marrow Transplantation, Vol. 28, No. 1, Voltarelli JC et al., "Beneficial effect of intravenous lidocaine in cutaneous chronic graft-versus-host disease secondary to donor lymphocyte infusion," pp. 97-99;

[0013] LUNG, Vol. 182, No. 1, 2004 Huang TK et al. "Surfactant lavage with lidocaine improves pulmonary function in piglets after HCl-induced acute lung injury", pp. 15-25;

[0014] RU2742505;

[0015] CN111150738;

[0016] CN103142643; and

[0017] CN104127397.

[0011]

[0018] A first object of the present invention was to identify one or more drugs for use in the treatment of autoimmune diseases or conditions in which treatment of the immune response resulting from disease or infection is required.

[0012]

[0019] A second and further object was to formulate such drugs for such uses.

[0013]

[0020] A third and further objective was to deliver such drugs in a manner and in dosages that would facilitate effective treatment. Summary of the Invention

[0014]

[0021] According to a first aspect of the invention there is provided lidocaine or a salt thereof, or articaine or a salt thereof, for use in the treatment of an autoimmune disease or condition in which an immune response due to disease or infection causes hyperinflammation.

[0015]

[0022] In one embodiment, this causes a cytokine storm.

[0016]

[0023] The autoimmune disease may be any of those listed below: Achalasia Addison's disease Adult Still's disease Agammaglobulinemia Alopecia areata Amyloidosis ·Ankylosing spondylitis ·Anti-GBM / anti-TBM nephritis Antiphospholipid syndrome ·Autoimmune angioedema Autoimmune autonomic neuropathy Autoimmune encephalomyelitis ·Autoimmune hepatitis ·Autoimmune inner ear disease (AIED) Autoimmune myocarditis Autoimmune oophoritis Autoimmune orchitis Autoimmune pancreatitis ·Autoimmune retinopathy ·Autoimmune urticaria Axonal and neuronal neuropathies (AMAN) Barrow's disease Behçet's disease Benign mucous membrane pemphigoid Bullous pemphigoid Castleman's disease (CD) Celiac disease Chagas disease Chronic inflammatory demyelinating polyneuropathy (CIDP) Chronic recurrent multifocal osteomyelitis (CRMO) Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis with polyangiitis (EGPA) Cicatricial pemphigoid ·Cogan's Syndrome ·Cold agglutinin disease Congenital heart block Coxsackie myocarditis ·CREST syndrome Crohn's disease ·Dermatitis herpetiformis ·Dermatomyositis Devic's disease (neuromyelitis optica) Discoid lupus Dressler Syndrome ·Endometriosis Eosinophilic esophagitis (EoE) Eosinophilic fasciitis ·Erythema nodosum Essential mixed cryoglobulinemia Evans syndrome ·Fibromyalgia Fibrinous alveolitis ·Giant cell arteritis (temporal arteritis) Giant cell myocarditis Glomerulonephritis Goodpasture's syndrome ·Granulomatosis with polyangiitis Graves' disease Guillain-Barre syndrome Hashimoto's thyroiditis ·Hemolytic anemia Henoch-Schönlein purpura (HSP) Herpes gestationis or pemphigoid gestationis (PG) Hidradenitis Suppurativa (HS) (Acne Inversa) Hypogammaglobulinemia IgA nephropathy IgG4-related sclerosing disease ·Immune thrombocytopenic purpura (ITP) Inclusion body myositis (IBM) ·Interstitial cystitis (IC) Juvenile arthritis Juvenile diabetes (type 1 diabetes) Juvenile myositis (JM) Kawasaki disease Lambert-Eaton Syndrome ·Leukocytoclastic vasculitis ·lichen planus ·Lichen sclerosus ·Ligny conjunctivitis Linear immunoglobulin A disease (LAD) Lupus Chronic Lyme Disease Meniere's disease Microscopic polyangiitis (MPA) ·Mixed connective tissue disease (MCTD) Mooren's ulcer Mucha-Habermann's disease Multifocal motor neuropathy (MMN) or MMNCB Multiple sclerosis ·Myasthenia gravis Myelin oligodendrocyte glycoprotein antibody disorder Myositis Narcolepsy Neonatal lupus Neuromyelitis optica ·Neutropenia Ocular cicatricial pemphigoid ·Optic neuritis Relapsing rheumatism (PR) ·PANDAS Paraneoplastic cerebellar degeneration (PCD) Paroxysmal nocturnal hemoglobinuria (PNH) Parry-Romberg syndrome Pars planitis (peripheral uveitis) ·Parsonage-Turner Syndrome ·Pemphigus Peripheral neuropathy Perivenous encephalomyelitis Pernicious anemia (PA) POEMS syndrome Polyarteritis nodosa ·Polyglandular syndrome type I, II, III Polymyalgia rheumatica Polymyositis Post-myocardial infarction syndrome Post-pericardiotomy syndrome Primary biliary cholangitis Primary sclerosing cholangitis Progesterone dermatitis ·psoriasis Psoriatic arthritis Pure red cell aplasia (PRCA) Pyoderma gangrenosum Raynaud's phenomenon Reactive arthritis Reflex sympathetic dystrophy Relapsing polychondritis ·Restless legs syndrome (RLS) Retroperitoneal fibrosis Rheumatic fever Rheumatoid arthritis ·sarcoidosis Schmidt syndrome ·Scleritis Scleroderma Sjögren's syndrome Sperm and testicular autoimmunity Stiff Body Syndrome (SPS) Subacute bacterial endocarditis (SBE) Susac syndrome ·Exchange ophthalmia (SO) ·Takayasu arteritis ·Temporal arteritis / giant cell arteritis Thrombocytopenic purpura (TTP) ·Thyroid eye disease (TED) Tolosa-Hunt Syndrome (THS) Transverse myelitis ·Type 1 diabetes ·Ulcerative colitis (UC) ·Undifferentiated connective tissue disease (UCTD) Uveitis ·Vasculitis ·Vitiligo Vogt-Koyanagi-Harada disease

[0024] Among these inflammatory diseases, those in which a cytokine storm syndrome is manifested are particular targets for treatment.

[0017]

[0025] Particularly preferred diseases for treatment are ARDS, COVID-19, and Long COVID.

[0018]

[0026] Lidocaine, also known as lignocaine, is sold under the trade name Xylocaine®. Lidocaine is a local anesthetic of the aminoamide type.

[0019]

[0027] As an approved drug, lidocaine is used intravenously, subcutaneously, topically, and orally.

[0020]

[0028] However, in these forms, lidocaine is not particularly well suited to target the lymphatic system and treat hyperinflammation by blocking the P2X7 receptor, thus halting the "cytokine storm" that can cause life-threatening ARDS in SARS-COV-2 disease (COVID-19) and other autoimmune diseases.

[0021]

[0029] A related drug, Articaine, is available in Europe with or without adrenaline. The epinephrine-free (adrenaline-free) form is sold under the trade name Ultracain D (4%). The epinephrine (adrenaline)-containing form is available in Europe under the trade name Supracain 4% with an epinephrine concentration of 1:200,000.

[0022]

[0030] Thus, according to a second aspect of the present invention there is provided a pharmaceutical formulation comprising lidocaine or a salt thereof or articaine or a salt thereof formulated to promote uptake by the lymphatic system by incorporation of one or more suitable excipients.

[0023]

[0031] Additionally, the pharmaceutical formulations are preferably packaged in a delivery form for buccal or sublingual administration along with instructions for use.

[0024]

[0032] The delivery form is preferably a unit dose with a volume of 1 ml or less, more preferably even 0.5 ml or less, containing a higher concentration of lidocaine or a salt thereof or articaine or a salt thereof compared to currently approved dosage forms of lidocaine and articaine.

[0025]

[0033] Thus, a unit dose of lidocaine contains 60-100 mg and a unit dose of articaine contains 40-100 mg.

[0026]

[0034] Preferably, but not necessarily, the lidocaine or articaine, or salts thereof, are dissolved in one or more lipophilic excipients, although uptake can be achieved using polar solvents.

[0027]

[0035] The use of surface modifiers such as long chain fatty acids and / or polyethylene glycol (PEG) and / or surfactants is preferred.

[0028]

[0036] Preferred delivery systems include, but are not limited to, nanoparticles, microparticles, liposomes, emulsifying drug delivery systems (EDDS) and variations thereof such as self-emulsifying drug delivery systems (SEDDS), self-microemulsifying drug delivery systems (SMEDDS), and self-nanoemulsifying drug delivery systems (SNEDDS).

[0029]

[0037] The simplest form is the drug in an oil such as a medium chain triglyceride.

[0030]

[0038] Thus, suitable formulations may include functional excipients such as lipophilic and polar solvents, co-solvents, viscosity modifiers, surfactants, sweeteners and flavorings.

[0031]

[0039] The formulations contain a sweetener, such as saccharin, and a flavoring, such as banana flavor, to improve palatability.

[0032]

[0040] A polar solvent is also used to facilitate its solubility in a low volume unit dose (1 ml or less, more preferably even 0.5 ml or less). A preferred polar solvent is ethanol.

[0033]

[0041] Additionally, one or more co-solvents are used. Suitable co-solvents include polyethylene glycol (Macrogol 400) and propylene glycol (E1520).

[0034]

[0042] A particular problem with the use of lidocaine is its known toxicity. Indeed, the advantage of articaine is that it is less toxic and more potent than lidocaine.

[0035]

[0043] Local anesthetics such as lidocaine can cause methemoglobinemia, which can occur when lidocaine is administered in high doses, typically greater than 4-5 mg / kg body weight in local anesthetics or plasma levels >5 mg / L.

[0036]

[0044] By administering lidocaine or articaine orally mucosally or sublingually, absorption occurs primarily through the lymphatic system rather than the venous system, avoiding toxic plasma levels and hepatic first-pass elimination, resulting in low plasma levels of lidocaine or articaine, thereby avoiding methemoglobinemia.

[0037]

[0045] It was essential to find an effective dose of either drug that did not cause toxicity.

[0038]

[0046] IC for blocking P2X7 receptors 50 To achieve this, a plasma concentration of 0.3 mM (66.07 μg / ml) is required. On the other hand, the maximum tolerable plasma concentration of lidocaine in humans is 0.02 mM (4.7 μg / ml), and above this level lidocaine becomes toxic. It is concluded that at least 50% inhibition of the P2X7 receptor cannot be achieved by administration of lidocaine using the traditional intravenous route. This also applies to articaine, although to a lesser extent.

[0039]

[0047] To solve this problem, applicants have formulated lidocaine (with the same rationale applied to articaine) into a high dose / low volume unit dose solution for oral mucosal or sublingual administration. The sublingual mucosa is known for its high permeability (more than 20 times the absorption rate compared to human skin) and furthermore the mouth and floor of the mouth are highly concentrated with lymph nodes making them ideal for targeting the lymphatic and immune systems.

[0040]

[0048] An effective adult unit dose of lidocaine delivered buccal or sublingually was found to be 60-100 mg delivered 4-6 times daily. The goal was to provide an effective amount of lidocaine at <4.7 μg / ml in plasma.

[0041]

[0049] Given the higher potency of articaine, the equivalent dose is 40-67 mg delivered 4-6 times daily. Due to its lower toxicity, dosages equivalent to lidocaine (60-100 mg) could also be achieved 2-4 times daily.

[0042]

[0050] To demonstrate the suitability of such a delivery method, the lidocaine formulation was modified from the Astra Zeneca Xylocaine 10% spray formulation by increasing the concentration of lidocaine from 10% to 25%.

[0043]

[0051] The formulation was delivered from a small single unit dose sealed vial (0.4 ml volume) for delivery as droplets rather than delivering a spray.

[0044]

[0052] It was important to deliver a unit dose of 60-100 mg of lidocaine in a volume of 0.5 ml or less.

[0045]

[0053] For articaine, the equivalent unit dose was 40-67 mg of articaine in a volume of 0.5 ml or less, but due to its low toxicity, doses of up to 100 mg could be administered in this volume.

[0046]

[0054] Lidocaine formulations that are significantly more concentrated than current formulations contain greater than 10% lidocaine by volume, more preferably greater than 20% by volume, typically 25% by volume, which has the advantage of avoiding the poorly tolerated mouth fullness and associated hypersalivation that occurs with the standard IV formulation (10% concentration).

[0047]

[0055] Articaine formulations are also more concentrated than current formulations, containing greater than 4% by volume, more preferably greater than 8% by volume, and typically 10% or more by volume.Articaine formulations can also be provided in unit dose form.

[0048]

[0056] According to a third aspect of the present invention, there is provided a method of treating a subject suffering from COVID-19 or an autoimmune disease or condition in which an immune response resulting from disease or infection leads to a cytokine storm, comprising administering to the subject an effective amount of lidocaine or a salt thereof or articaine or a salt thereof that targets the lymphatic system in a suitable high dose / low volume unit dosage form.

[0049]

[0057] High dose / low volume unit dosage form means that the relative concentration of lidocaine or a salt thereof or articaine or a salt thereof is significantly higher than existing dosage forms (10% for lidocaine or a salt thereof, 4% for articaine or a salt thereof) in a unit dosage volume of 1 ml or less, more preferably 0.5 ml or less.

[0050]

[0058] Preferably, lidocaine or a salt thereof or articaine or a salt thereof is administered orally or sublingually.

[0051]

[0059] Preferably, the unit dose contains 60-100 mg of lidocaine or a salt thereof, or 40-100 mg of articaine or a salt thereof.

[0052]

[0060] Preferably, the unit dose has a volume of 0.5 ml or less.

[0053]

[0061] The treatment may be treatment of COVID-19, acute respiratory distress syndrome (ARDS), long COVID, or an autoimmune disease, particularly, but not limited to, scleroderma; dermatomyositis; Parkinson's; and psoriasis.

[0054]

[0062] Most preferably, the treatment is for the treatment of Long COVID or symptoms thereof including fatigue, moderate to severe shortness of breath, pain, insomnia, difficulty breathing, dizziness, muscle spasms and / or palpitations.

[0055]

[0063] The primary goal of treatment is to reduce systemic hyperinflammation, which can be determined by measuring biomarkers such as interleukin 6, ferritin, leukocytes, neutrophils, lymphocytes, platelets, C-reactive protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer.

[0056]

[0064] Various aspects and embodiments of the invention are further described below with reference to the detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057]

[0065] The investigational formulation is illustrated in Example 1. EXAMPLES

[0058] Example 1a formulation

[0066] active ingredient Lidocaine: 100mg

[0067] Excipients: Lipophilic solvent – ​​Levomenthol Polar solvent - Ethanol 96% 241mg / ml Co-solvent - Polyethylene glycol (Macrogol 400) Co-solvent - Propylene glycol (E1520) ·Sweeteners - Saccharin (E954) Flavoring - Banana flavor Diluent - (purified) water Total 0.4ml

[0068] The formulations of the present invention were used "off-label" to treat multiple patients as shown in Example 2 to determine their efficacy.

[0059]

[0069] Example 1b As in Example 1a except the active ingredient was articaine.

[0060] Example 2 Patient Clinical Trial Data

[0070] In the Netherlands, 22 patients were treated with the formulation of Example 1a as follows.

[0061]

[0071] Ten patients had symptoms of COVID-19 (tested positive and diagnosed by a general practitioner). All ten patients presented with early signs of respiratory distress; tachypnea (>30 breaths per minute), high fever, and dry cough, as well as a reduced SpO2 <90. The patients responded well to sublingual lidocaine, which allowed them to avoid hospitalization for COVID-19.

[0062]

[0072] Six patients had post-COVID respiratory complaints. Patients experienced long-term complaints ranging from cough, fatigue, and shortness of breath to anxiety and physical limitations.

[0063]

[0073] The six patients had a variety of autoimmune diseases, including: · One patient had rheumatoid arthritis; · One patient had scleroderma; · One patient had dermatomyositis; · One patient had Parkinson's disease; Two patients had psoriasis.

[0064]

[0074] All patients received the formulation described in Example 1a above up to six times daily for up to two weeks.

[0065]

[0075] A total of 8 of 22 patients responded to the treatment within hours and recovered uneventfully within a few days.

[0066]

[0076] Ten patients with COVID-19 and six patients with post-COVID respiratory complaints recovered completely within two weeks.

[0067]

[0077] Five of six patients with identified autoimmune diseases experienced significant improvement two weeks after treatment, and all were free of side effects.

[0068]

[0078] Only one patient showed slight improvement, a 56-year-old male with severe rheumatoid arthritis. conclusion

[0079] Administration of lidocaine to target the subject's lymphatic system appears to be effective in treating COVID-19 and Long COVID. The sublingual / oral mucosal approach is a simple, effective, and non-invasive technique. A high concentration, low volume unit dose of lidocaine >10% in a small volume of <0.5ml is optimal.

Claims

1. A pharmaceutical formulation for treating COVID-19 or acute respiratory distress syndrome (ARDS), comprising lidocaine or a salt thereof, wherein the lidocaine or a salt thereof is formulated with a lipophilic excipient for subcutaneous, buccal mucosa or sublingual delivery, targeting the lymphatic system, and contains 40-100 mg of lidocaine or a salt thereof as a unit dose in a volume of 0.5 ml or less.

2. The pharmaceutical formulation according to claim 1, wherein the lipophilic excipient is menthol.

3. The pharmaceutical formulation according to claim 1 or 2, further comprising a polar solvent.

4. The pharmaceutical formulation according to claim 3, wherein the polar solvent is ethanol.

5. The pharmaceutical formulation according to claim 1 or 2, further comprising one or more co-solvents.

6. The pharmaceutical formulation according to claim 5, wherein the one or more co-solvents comprise polyethylene and polypropylene glycol.

7. The pharmaceutical formulation according to claim 1 or 2, further comprising a sweetener and a flavoring agent.

8. The pharmaceutical formulation according to claim 1 or 2, comprising a solution of at least 20% by weight of lidocaine or a salt thereof.