Lidocaine hydrochloride nasal composition for epilepsy treatment

Abstract

The present invention relates to a lidocaine hydrochloride nasal composition associated with pharmacologically acceptable components in a portion of 1 ml to 1.8 ml of a highly concentrated, stable, clear transparent solution, with concentrations of lidocaine hydrochloride varying from around 1000 mcg / 0.05 ml to around 1500 mcg / 0.05 ml per drop, with a pH varying between around 6.0 and around 7.0 and a viscosity varying from around 1 to 100 cps, said combination being suitable for systemic intranasal release, administered in drops or assisted devices - metered dose inhalers, mDIs, around (0.05 ml to 0.20 ml) or (0.0166 ml to 0.05 ml = 1 to 3) being the necessary minimum for a therapeutic effect. Use thereof is recommended for mammals heavier than 200 g.

Description

[0001] Nasal composition of lidocaine hydrochloride for the treatment of epilepsy

[0002] FIELD OF INNOVATION

[0003]

[0001] The invention patent refers to the intranasal composition of lidocaine hydrochloride associated with pharmacologically acceptable components, in monotherapeutic use or / in combinations, administered in drops or assisted devices - metered dose inhalers (mDIs).

[0004] FUNDAMENTALS OF INNOVATION I

[0005]

[0002] Epilepsy is a common neurological condition in which abnormal electrical discharges in the brain cause a person to have recurrent seizures. The authors of this review evaluated two types of epileptic seizures: partial-onset seizures (which begin in one area of ​​the brain) and generalized tonic-clonic seizures (which begin in both cerebral hemispheres simultaneously).

[0006]

[0003] Several decades have been devoted to studying the pathophysiology of epilepsy, but knowledge in this area has only contributed to a partial understanding of the mechanisms involved. Data from the World Health Organization indicate a worldwide prevalence of epilepsy of approximately 50 million people. An epileptic seizure is a period of abnormal synchronous excitation of a population of neurons. The balance between control systems that prevent neurons from firing excessive action potentials and other systems that facilitate excitation maintains the proper functioning of the nervous system. Ion channels are involved in the process of neuronal excitability and communication between them through the release of neurotransmitters. However, only recently has direct evidence emerged of the importance of channel dysfunctions in the natural emergence of this neuronal disorder.Genetic investigations have led to the classification of some epileptic syndromes as channelopathies and, consequently, increased our understanding of the pathophysiology of seizure disorders. Epileptic channelopathies are caused by mutations in the genes encoding ion channels, both voltage-sensitive channels (Na+, K+, Ca2+, and CI-) and ligand-sensitive channels, such as the nicotinic acetylcholine receptor (nAChR) and the ionotropic γ-aminobutyric acid receptor (GABAA). These mutations generally cause changes in the electrophysiological properties of the channels, leading to increased excitability or decreased neuronal inhibition. This imbalance in the functioning of neuronal networks leads to the onset of epileptic seizures, which are the most prominent manifestation of epilepsy.

[0007] Antiepileptic drugs act on several molecular targets, modulating the activity of voltage-sensitive ion channels (Na+ and Ca2+ channel inhibitors and K+ channel activators), increasing neuronal inhibition mediated by GABAA receptors (GABAergic modulators and drugs that increase GABA availability), or decreasing synaptic excitation (glutamate receptor inhibitors). The biophysical changes in channel behavior induced by antiepileptic drugs are often opposite to the effects generated by mutations. However, given the inability of currently available drugs to cure epilepsy, the great challenge for scientific research is the discovery of a treatment capable of preventing or reversing epilepsy, as it is currently possible to control seizures in approximately 70% of people with epilepsy. In most of these people, seizures are controlled with a single antiepileptic drug (monotherapy).Choosing the first antiepileptic medication for someone newly diagnosed with epilepsy is crucial. This choice should take into account the high-quality evidence available about the effectiveness and side effects of each medication. It's also important to compare the different types of medications available for different types of seizures.

[0008]

[0005] One of the alternatives for the treatment of epilepsy studied by the present invention is Lidocaine Hydrochloride. Lidocaine Hydrochloride has properties of controlling status epilepticus when refractory to other treatments due to its mechanism of action. There are numerous studies on the effectiveness of the use of lidocaine in the treatment of epilepsy, in this case, only three examples will be cited, being non-patent references, where, SUCCESSFUL MANAGEMENT OF INTRACTABLE EPILEPSY WITH LIDOCAINE STRIPS AND CONTINUOUS SUBCUTANEOUS INFUSION OF LIDOCAINE (https: / / doi.Org / 10.1111 / j.0013-9580.2004.17304.x). LIDOCAINE FOR STATUS EPILEPTICUS IN ADULTS (https: / / www.sciencedirect.com / science / article / pii / S1059131115001661). LIDOCAINE-DEPENDENT EARLY INFANTILE EPILEPTIC CEPHALOPATHY WITH HYPONATREMIA AND HIGHLY SUPPRESSED EEG. (https: / / doi.Org / 10.1 111 / j.1528-1157.2000.tb02270.x).

[0009] LIDOCAINE IN REFRACTORY STATUS EPILEPTICUS: CONFIRMATION OF EFFICACY WITH EEG MONITORING

[0010] CONTINUOUS, (https: / / d0i.0rg / l 0.1111 / J.1528-1157.1992.tb02200.x) etc.

[0011]

[0006] In analyzing the non-patent references in proving the efficiency of the use of lidocaine in the treatment of epilepsy, despite the many studies, tests and research, they can be divided into 8 (eight) forms of administration, namely: the one that adopts adjunct treatment with intravenous lidocaine; the one that adopts adjunct treatment with subcutaneous lidocaine infusion; the one that adopts adjunct treatment with lidocaine tapes; the one that adopts the treatment with a parenteral preparation of lidocaine altered to the viscous type to allow administration by gastric tube; the one that adopts adjunct treatment with intravenous lidocaine; the one that adopts adjunct treatment with subcutaneous lidocaine infusion and other substances and the one that adopts the treatment with a parenteral preparation of lidocaine altered to the viscous type to allow administration by gastric tube with other substances different from the present innovation.

[0012]

[0007] Other characteristics of these treatments are the association of lidocaine and other substances different from the present invention.

[0013]

[0008] These administrations in reducing epileptic seizures, although effective, are fraught with problems, such as: a) It has an inverse relationship with the degree of non-ionization, b) Need for anesthetic reapplication, c) Need for bleeding control, d) Irritation at the application site is the most common adverse event associated with the use of lidocaine patches.

[0014]

[0009] Other problems include gastric problems, seizures, and heart problems caused by excessive lidocaine use. Systemic toxicity control is required due to replication. Local anesthetics can be toxic depending on the dose administered and the degree of systemic absorption. These reactions may be caused by elevated plasma drug levels caused by excessive doses.

[0015]

[0010] Another problem would be that all of these treatments use an excessive amount of lidocaine, as there is no consensus on the concentration of lidocaine necessary to block sodium channels in neurons. A classic study is by Ragsdale et al., published in 1994, where they examined the inhibition of sodium channels by lidocaine and found that the IC50 (50% inhibitory concentration) of lidocaine is in the range of 10 to 100 micromolar (pM). The IC50 is the concentration at which 50% of the sodium channels are blocked. Ragsdale, D.S., McPhee, J.C., Scheuer, T., & Catterall, W.A. (1994). Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science, 265(5179), 1724-1728. Another study that may be useful is: Butterworth, J.F., & Strichartz, G.R. (1990). Molecular mechanisms of local anesthesia: a review. Anesthesiology, 72(4), 711-734. FUNDAMENTALS OF INNOVATION II

[0016]

[0011] Over the years, many studies have been carried out to explore the advantages and disadvantages of intranasal (IN) drug administration, characterization studies and comparison of pharmacokinetic data in relation to other routes, as well as to evaluate the characteristics of the formulations to obtain the expected therapeutic effect. The IN route presents itself as a route that offers numerous advantages over intravenous (IV), subcutaneous (SC), transmucosal or rectal administration. (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery : An efficient and non-invasive route for systemic administration Focus on opioids - Pharmacol Ther - Elsevier Inc.; 2012;134(3) :366-79) and (Veldhorst-janssen NML, Fiddlers AAA, Kuy PM Van Der, Kessels AGH, Theunissen HMS, Hulst RRWJ Van Der, et al.Pharmacokinetics, Analgesic Effect, and Tolerability of a Single Preprocedural Dose of Intranasal Fentanyl in Patients Undergoing Drain Removal After Breast Reduction or Augmentation Surgery: A Prospective, Randomized, Double-Blind, Placebo- Controlled Stu. Clin Ther). Excerpta Medica Inc.; 2010;32(7):1427-36).

[0017]

[0012] Thus, the administration of drugs via the IN route has been associated with ease of administration, rapid onset of action, possibility of self-administration, is a non-invasive route, has high acceptability by patients, is easy to administer to patients whose oral intake is compromised (for example due to nausea and vomiting), avoids first-pass hepatic metabolism, gastrointestinal metabolism (GI) and presents, in most cases, high bioavailability (BD). (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration Focus on opioids. Pharmacol Ther. Elsevier Inc.; 2012;134(3):366-79); (Mistry A, Stolnik S, Ilium L. Nose-to-brain delivery: Investigation of the transport of nanoparticles with different surface characteristics and sizes in excised porcine olfactory epithelium.Mol Pharm. 2015) e (D HOEKMAN, JOHN, SRIVASTAVA, PRAMOD, and J Y HO R. Aerosol Stable Peptide- Coated Liposome Nanoparticles: A Proof-of-Concept Study with Opioid Fentanyl in Enhancing Analgesic Effects and Reducing Plasma Drug Exposure. J Pharm Sci. 2014;103(8):206-21 ).

[0018]

[0013] The IN route is characterized by a high absorption potential for lipophilic drugs with molecular weight (MW) below 1 kDa, presenting a poor permeability to hydrophilic drugs with high molecular weight (proteins and peptides). Additionally, absorption in the nasal cavity is limited by mucociliary clearance, by the enzymatic activity of the nasal mucosa (especially in protein and peptide drugs), by the action of some pharmacological agents (especially those that act on adrenergic or cholinergic receptors, which influence nasal blood flow) and environmental factors such as tobacco smoke. (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration Focus on opioids. Pharmacol Ther. Elsevier Inc.; 2012;134(3):366-79).

[0019]

[0014] Clinical PK data for three drug classes reviewed by Veldhorst et al. demonstrated that, after the IV route, the IN route showed the highest BD in the shortest time (IV > IN > oral). (Veldhorst-janssen NML, Fiddelers AAA, Kuy PM Van Der, Neef C, Marcus MAE. A Review of the Clinical Pharmacokinetics of Opioids, Benzodiazepines, and Antimigraine Drugs Delivered Intranasally. Clin Ther. Excerpta Medica Inc.; 2009;31 (12):2954-87).

[0020]

[0015] Thus, in patients in whom IV access is difficult or not justified, IN administration is a viable alternative, for example in the relief of acute pain, migraines, and seizures. This route offers rapid systemic absorption in association with the possibility of delivering drugs directly from the nasal cavity to the CNS, partially bypassing the blood-brain barrier (BBB). (Touitou E, Ilium L. Nasal drug delivery, Drug Deliv transi Res. 2012;3:1-3). In this sense, there is an increasing number of molecules being studied and marketed with formulations for nasal administration. (Ilium L. Nasal drug delivery — Recent developments and future perspectives. J Control Release. Elsevier BV; 2012;161 (2):254-63).

[0021]

[0016] Thus, according to a report by Global Industry Analysts, with the growth of trade and research in this area, the North American market for intranasal drugs is expected to reach 5.2 trillion dollars in 2017. (Expanding Therapeutic Applications to Drive the US Intranasal Drug Delivery Market, According to New Report by Global Industry Analysts, Inc. GIA announces the release of a comprehensive US market report on Intranasal Drug Delivery. 2012;2-4).

[0022]

[0017] In this context, it is important to monitor the growing number of formulations that have been developed, getting closer and closer to what is the “ideal formula”: low MW drugs, high lipophilicity, non-ionized at physiological pH, the most effective treatment regimen, vehicles, absorption promoters and administration devices.

[0023]

[0018] To better contextualize the topic, it is important to understand the main characteristics of the nasal mucosa, such as its site of drug absorption, its transport pathways to the bloodstream and the central nervous system, and the main characteristics of drugs and formulations to optimize their therapeutic effect. These topics will be addressed later in the remaining introductory sections.

[0024]

[0019] Nasal mucosa as a site of drug absorption. The human nasal cavity has a total area of ​​150 cm2 and a capacity of 15-20 ml. The two nasal cavities, divided by the nasal septum, are subdivided into three areas: nasal vestibule, olfactory area, and respiratory area (Hum L. Is nose-to-brain transport of drugs in man a reality? Pharm Pharmacol. 2003;(lllum 2003):3-17) and (Pires A, Fortuna A, Alves G, Falcão A. Intranasal Drug Delivery: How, Why, and What for J Pharm Pharm Sc. On the lateral walls of the nasal cavity are three shell-shaped ridges that increase the surface area of ​​the nasal mucosa, the turbinates (Seeley, Rod R., Stephens Trent D TP. Respiratory system. In: Seeley, RR, Stephens, TD and Tate, P. (Ed.) Anatomy and Physiology. 6th ed. Loures, Lusociência - Edições Técnicas e Científicas L, editor. 2003. 826-828 p).It presents as a highly vascularized area, which enhances rapid and effective absorption (1 Castile J, Cheng Y, Simmons B, Perelman M, Smith A, Watts P. Development of in vitro models to demonstrate the ability of PecSys, an in situ nasal gelling technology, to reduce nasal run-off and drip. Drug Dev Ind Pharm. 2013;39(May 2012):816-24) and (Corli O, Roberto A. Pharmacological and clinical differences between transmucosal fentanyl formulations for the treatment of breakthrough cancer pain: a review article. Ed MINERVA MEDICA. 2014;80(10):1123-34.). However, the nasal mucosa has anatomical limitations regarding the absorption of large volumes of solution, which may even reduce the potential efficacy of the drug.

[0025]

[0020] Thus, only the administration of 0.15-0.2 ml per nostril is shown to be efficiently absorbed by the nasal mucosa; however, part of the administered volume is lost, thus losing part of the drug, which leads to a decrease in BD (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration. Focus on opioids. Pharmacol Ther. Elsevier Inc.; 2012;134(3):366-79) - (Castile J, Cheng Y, Simmons B, Perelman M, Smith A, Watts P. Development of in vitro models to demonstrate the ability of PecSys, an in situ nasal gelling technology, to reduce nasal runoff and drip. Drug Dev Ind Pharm. 2013;39(May 2012):816-24) - (Borland M, Milsom S, Esson A. Equivalency of two concentrations of fentanyl administered by the intranasal route for acute analgesia in children in a pediatric emergency department A randomized controlled trial. Pediatr Emerg Med. 2011; 23:202-8).Diversos autores, nomeadamente Ilium (2000), Pires et al. (2009), Delyle et al. (2012) e Touitou et al. (2012), descrevem a cavidade nasal com detalhe (Grassin-delyle S, Buenestado A, Naline E, Faisy.

[0026] C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration Focus on opioids. Pharmacol Ther. Elsevier Inc.; 2012;134(3):366-79) - (Touitou E, Ilium L. Nasal drug delivery, drug Deliv transl Res. 2012; 3:1 -3) - (Pires A, Fortuna A, Alves G, Falcão A. Intranasal Drug Delivery: How, Why and What for J Pharm Pharm Sc. 2009;12(3):288-311 ) - (Ilium L, Ph BS, Sc

[0027] D. Drug transport from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000;11:1-18). This introductory review provides only a summary to contextualize the topic and understand the most important anatomical and histological characteristics for drug absorption.

[0028]

[0021] The respiratory tract extends throughout the middle and lower nasal cavity and is considered the largest site of drug absorption into the bloodstream due to its high surface area (120 to 150 cm 2) e o seu elevado grau de vascularização (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery: Na efficient and non-invasive route for systemic administration Focus on opioids. Pharmacol Ther. Elsevier Inc.; 2012;134(3):366-79) - (D. Hoekman, John JYHR. Enhanced Analgesic Responses After Preferential Delivery of Morphie and Fentanyl to the Olfactory Epithelium in Rats. Anesth Analg. 2011 ;113(3) :641 — 51 ).

[0029]

[0022] This area is lined by three types of epithelium: the most anterior part of the respiratory area is lined by stratified epithelium, which is followed by a transitional epithelium and converts in the posterior part of the cavity into a pseudostratified epithelium. The pseudostratified respiratory epithelium is composed of four types of cells: ciliated columnar cells, non-ciliated columnar cells, mucus-secreting goblet cells, and basal cells. These epithelial cells have intercellular junctions on the apical surface (cohesion junctions) and are covered by cilia responsible for propelling the mucus towards the nasopharynx; They also have microvilli that greatly increase the absorption area of ​​the respiratory epithelium (Grassindelyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration Focus on opioids. Pharmacol Ther.Elsevier Inc .; 2012;134(3):366-79) - (Ilium L, Ph BS, Sc D. Drug transport from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000; 11 :1-18). The integrity of tight junctions depends on the concentration of extracellular calcium ions, so that calcium chelating substances can open these junctions, functioning as absorption promoters (Mistry A, Stolnik S, Ilium L. Nose-to-Brain Delivery: Investigation of the Transport of Nanoparticles with Different Surface Characteristics and Sizes in Excised Porcine Olfactory Epithelium. Mol Pharm. 2015) and (Ilium L. Is nose-to-brain drug transport in humans a reality? Pharm Pharmacol. 2003; (Ilium 2003):3— 17.).

[0030]

[0023] Regarding the olfactory epithelium, this is located in the upper nasal cavity, between the brain and the respiratory epithelium, and corresponds to only 3-10% of the area of ​​the nasal cavity in humans.

[0031]

[0024] It presents as a narrow channel, only 1-2 mm wide, and is responsible for odor detection. Therefore, the composition and organization of its epithelial layers is designed to maximize air access to the neuronal structures that detect smell (D. Hoekman, John JYHR. Enhanced Analgesic Responses After Preferential Delivery of Morphie and Fentanyl to the Olfactory Epithelium in Rats. Anesth Analg. 2011 ;113(3) :641 — 51 ). The olfactory epithelium is a modified (pseudostratified) respiratory epithelium that contains olfactory sensory neurons, supporting cells, and basal cells. Below the basement membrane is the lamina propria, which contains blood vessels, olfactory axon bundles, trigeminal nerve fibers, and Bowman's glands (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al.Pharmacology & Therapeutics Intranasal drug delivery: An efficient and noninvasive route for systematic administration Focus on opioids. Pharmacol Ther. Elsevier Inc .; 2012;134(3):366-79) - (D. Hoekman, John JYHR. Enhanced analgesic responses after preferential delivery of morphie and fentanyl to the olfactory epithelium in rats. Anesth Analg. 2011 ;113(3):641 — 51 ) - (Ilium L. Is nose-to-brain drug transport in humans a reality Pharm Pharmacol. Olfactory sensory neurons, also known as olfactory receptor cells, are covered by cilia that line the epithelium. Each neuron gives rise to a single axon of unmyelinated fibers that penetrates the basement membrane to join with other axons and form large bundles in the lamina propria.

[0032]

[0025] From the literature we know that the olfactory epithelium contains interneuronal channels that make it more conducive to the transport of molecules, compared to the respiratory epithelium. These channels are created by the space surrounding the olfactory neurons that forms a kind of fluid-filled pathways 10 to 15 nm in diameter (D HOEKMAN, JOHN, SRIVASTAVA, PRAMOD, and JY HO R. Aerosol-stable peptide-coated liposome nanoparticles: a proof-of-concept study with opioid fentanyl in enhancing analgesic effects and reducing plasma drug exposure. J Pharm Sci. 2014;103(8):206-21.). The blood supply to the nasal cavity comes from the external carotid artery system (sphenopalatine plexus and facial arteries) and internal (via the ophthalmic artery) through an abundant network of blood capillaries located in the lamina propria.Venous return occurs through the sphenopalatine plexus, facial and ophthalmic veins, and finally the internal jugular vein, which connects to the heart through the subclavian vein and superior vena cava. This blood circuit, which affects drugs absorbed into the bloodstream from the nasal cavity, explains why the hepatic first-pass effect, which is the effect of drugs administered orally, for example, does not occur (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration. Focus on opioids. Pharmacol Ther.

[0033]

[0026] Drug transport from the nasal mucosa to the brain and CNS. To better understand the possible transport pathways between the nasal mucosa and the CNS, it is imperative to also understand some of the characteristics of the latter. The brain is protected by two bony structures: the skull and the spinal column, and is surrounded by the subarachnoid space, in which cerebrospinal fluid (CSF) circulates. This space is surrounded by the meninges, which consist of three membranes: the dura mater, which lies beneath the skull; the pia mater, which lies above the brain; and between the two is the arachnoid mater. Between the pia mater and the arachnoid mater is the subarachnoid space.

[0034]

[0027] CSF is mostly produced by the four ventricles of the choroid plexus, and its production rate is equal to the rate of absorption into the bloodstream at the arachnoid microvilli (21 ml / h) (Ilium L. Is nose-to-brain transport of drugs in man a reality? Pharm Pharmacol. 2003;(lllum 2003):3-17) and (Ilium L, Ph BS, Sc D. Transport of drugs from the nasal cavity to the central nervous system. A drug administered via IN can be absorbed into the bloodstream and reach the systemic circulation, being subsequently eliminated by the usual elimination mechanisms. The drug can also reach the CNS from the bloodstream by transposition of the BBB, which is characterized by being a complex and dynamic structure with very restricted permeability, which prevents the passage of toxic substances to the CNS. This is the so-called systemic route to the brain.Once in the brain, the drug can also be eliminated from the CSF into the peripheral circulation. To cross the BBB by passive diffusion, drugs must exhibit a relative degree of lipophilicity (corresponding to an ideal oil / water partition coefficient (logP) of 2) and a MW of 400 Da or less (21). Modifications can be made, such as binding the drug molecules to transport proteins such as transferrin or a polycationic molecule, which will bind preferentially to the negatively charged endothelium, facilitating transport across the BBB.

[0035]

[0028] Drugs absorbed from the olfactory region of the nasal cavity into the CSF or into the brain parenchyma have to cross the olfactory epithelium, and depending on the route followed, also the arachnoid membrane that surrounds the subarachnoid space (Mistry A, Stolnik S, Ilium L. Nose-to-Brain Delivery: Investigation of the Transport of Nanoparticles with Different Surface Characteristics and Sizes in Excised Porcine Olfactory Epithelium.11 :1 — 18.)- Drugs can follow 3 different pathways in the olfactory epithelium: (i) Transcellular route: molecules can cross epithelial cells through passive diffusion towards a lower concentration gradient (lipophilic drugs) or through mediated processes, such as active transport by transporters responsible for the influx or efflux of peptides, organic anions and cations (including P-glycoprotein, the organic anion transporter and the organic cation transporter); (ii) Paracellular route through the cohesion junctions between epithelial cells, whose role is not only to ensure the mechanical cohesion of the epithelial cells, but also to regulate molecular transport through the space; (iii) via the olfactory nerve route, either paracellular or transcellular, through the olfactory neurons;Existe ainda uma quarta via de transporte, comum em ambos os epitélios, o transporte através do nervo trigémio (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery : An efficient and non-invasive route for systemic administration Focus on opioids. Pharmacol Ther. Elsevier Inc.; 2012;134(3):366-79) - (Mistry A, Stolnik S, Ilium L. Nose-to-Brain Delivery: Investigation of the Transport of Nanoparticles with Di ff erent Surface Characteristics and Sizes in Excised Porcine Olfactory Epithelium. Mol Pharm. 2015) - (Ilium L. Is nose-to-brain transport of drugs in man a reality ? Pharm Pharmacol. 2003;(lllum 2003):3-17) - (Ilium L, Ph BS, Sc D. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000; 11 :1-18).;

[0036]

[0029] Above details the representative scheme of the drug transport pathways from the nasal cavity to the CNS. Elimination pathways in the nasal cavity: mucociliary clearance and enzymatic degradation; after IN administration, drugs can follow 3 pathways: 1 - transport through the respiratory epithelium into the bloodstream, followed by transport through the BBB (systemic pathway); 2 - Olfactory epithelial pathway or nervous pathway; 3 - Transport through the trigeminal nerve located in both epithelia (trigeminal pathway);

[0037]

[0030] It is known from the literature that drugs can use more than one route until they reach the CNS. Generally, the rapid appearance of a drug in the CSF indicates the use of routes other than the transcellular route of the olfactory nerve, as this route is associated with slow transport.

[0031] The rapid appearance of small, low MW molecules from the nasal cavity to the CSF is associated with the extracellular transport pathway. We then talk about the paracellular transport of molecules that involves the passage through the tight junctions of the epithelium and the olfactory nerve fibers until the CSF is reached, and other regions of the CNS (Mistry A, Stolnik S, Ilium L. Nose-to-brain delivery: investigation of the transport of nanoparticles with different surface characteristics and sizes in Excised Porcine Olfactory Epithelium. Mol Pharm. 2015) and (Ilium L. Nasal drug delivery — Recent developments and future prospects. J Control Release. Elsevier BV; 2012;161 (2):254-63).As reviewed by Ilium et al, Hoekman et al, with several molecules, a few minutes after IN administration the amount of drug that reaches the CNS, namely the CSF, is higher than the amount that reaches the plasma at the same time, which indicates that the drugs can bypass the passage to the bloodstream and pass directly to the brain (D HOEKMAN, JOHN , SRIVASTAVA, PRAMOD, and JY HO R. Aerosol Stable Peptide-Coated Liposome Nanoparticles: A Proof-of-Concept Study with Opioid Fentanyl in Enhancing Analgesic Effects and Reducing Plasma Drug Exposure. 2000; 11 :1-18).

[0038]

[0032] The ability to deliver a therapeutically valuable drug quantity from the nasal cavity to the brain for the treatment of neurological diseases depends on the availability of efficient drug delivery systems (Mistry A, Stolnik S, Ilium L. Nose-to-Brain Delivery: Investigation of the Transport of Nanoparticles with Different Surface Characteristics and Sizes in Excised Porcine Olfactory Epithelium. Mol Pharm. 2015;). Note that the IN route of administration is not appropriate for all types of compounds, since the main factors for overcoming biological barriers are the intrinsic physicochemical properties of each molecule. However, IN absorption can be improved by the use of absorption enhancers and optimization of pharmaceutical formulations.

[0039]

[0033] MW is a limiting factor for paracellular passage through cohesion junctions. For drugs with MW less than 300 Da, nasal absorption is rapid and is practically uninfluenced by other physicochemical properties, while molecules with MW above 1 kDa are absorbed very slowly (BD of between 0.5% and 5%) (Ilium L. Is nose-to-brain transport of drugs in man a reality? Pharm Pharmacol. 2003;(lllum 2003):3-17) - (Costantino HR, Ilium L, Brandt G, Johnson PH, Quay SC. Intranasal delivery: Physical and therapeutic aspects. Int J Pharm. 2007; 337:1-24). In molecules with a MW between 300 Da and 1 kDa, lipophilicity is a key characteristic in absorption, as lipophilic molecules diffuse freely through the epithelium, whereas hydrophilic molecules have to use the paracellular pathway to do so (Grassindelyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al.Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration Focus on opioids. Pharmacol Ther. Elsevier Inc.; 2012;134(3) :366-79) and (Costantino HR, Ilium L, Brandt G, Johnson PH, Quay SC. Intranasal delivery: Physicochemical and therapeutic aspects. Int J Pharm. 2007; 337:1-24).

[0040]

[0034] In order to understand this dependence of drug properties, studies were carried out with molecules of different degrees of lipophilicity. Hoekman et al. compared fentanyl, lipophilic (logP = 3.9) deposited in the olfactory region, and hydrophilic morphine (logP = 0.8). As expected, a different distribution pattern was observed, with fentanyl being the drug that reached higher plasma levels in the shortest time (D. Hoekman, John JYHR. Enhanced Analgesic Responses After Preferential Delivery of Morphie and Fentanyl to the Olfactory Epithelium in Rats. Anesth Analg. 2011 ;113(3):641— 51 .).

[0041]

[0035] The degree of ionization is also involved in drug diffusion, as only the non-ionized fraction is capable of diffusing through biological membranes (Costantino HR, Ilium L, Brandt G, Johnson PH, Quay SC. Intranasal delivery: Physicochemical and therapeutic aspects. Int J Pharm. 2007; 337:1-24.). In molecules such as proteins (high MW and non-zero charge at physiological pH), diffusion through biological membranes is not favored and, therefore, the molecules adopt alternative mechanisms, such as mediated transport or the paracellular pathway. In the case of small molecules that are weak acids or bases, the degree of ionization can be controlled during formulation by using a vehicle that provides the solution with a specific pH to solubilize the active ingredient, in order to obtain the drug in its non-ionized state.Since the average pH of the nasal cavity is approximately 6.3, basic drugs (pKa above 7.3), in the absence of a buffer, are predominantly ionized, and in this form membrane diffusion is limited (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration Focus on opioids. Pharmacol Ther. Elsevier Inc.; 2012;134(3):366-79.).

[0042]

[0036] To increase BD, several strategies can be adopted for the formulation of drugs administered intravenously. To improve permeability and reduce elimination phenomena (enzymatic degradation, efflux, and mucociliary clearance), enzyme inhibitors and absorption promoters can be administered together with the active ingredient, or the chemical properties of the drug can be optimized. This can be achieved through the use of prodrugs, which are used to improve the stability and permeability of drugs across the nasal epithelium. In this sense, hydrophilic groups can be added to increase water solubility in the case of very poorly soluble compounds, or hydrophobic groups can be added to increase lipophilicity and the ability of the drug to cross biological membranes (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al.Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration. Focus on opioids. Pharmacol Ther. Elsevier Inc .; 2012;134(3):366-79.). The use of solubilizing agents may also be considered.

[0043] STATE OF THE TECHNIQUE

[0044]

[0037] As the present invention relates to a compound containing lidocaine hydrochloride in the association of vasoconstrictor and, or in the association of solvents administered by intranasal induction, some documents disclose similar techniques, such as compositions of anesthetics and vasoconstrictors for nasal administration with other excipients, such as for example the document US005453445A of 09 / 26 / 1995, A dispensable pharmaceutical composition in aerosol that contains consisting essentially of a combination of lidocaine free base, a pharmacologically acceptable phenylephrine acid addition salt and a pharmacologically acceptable organic solvent, all dissolved in a propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane of the formula CFCFF (HFC 134a) and 1,1,1,2,3,3,3-heptafluoropropane of the formula CFCHFCF (HFC-227) or a combination thereof referred to propellants,Suitable for dispensing through a clear, pressure-containing metering valve container, this avoids the need for pre-mixing of individual solutions by the physician immediately before use. The phenylephrine salt is preferably the hydrochloride, and the solvent is preferably ethanol, although other pharmacologically acceptable solvents and pharmacologically acceptable acid addition salts of phenylephrine may be used. The lidocaine free base aids in solubilizing the phenylephrine salt and keeps it in solution in the propellant. Document US005942543A of 08 / 24 / 1999, a topical anesthetic includes about 1-10% by weight lidocaine hydrochloride, about 0.01-0.10% by weight epinephrine, and about 0.25-4% by weight tetracaine hydrochloride.preferably in an aqueous base with about 2% benzyl alcohol or in a gel including about 3% hydroxyethyl cellulose. The topical anesthetic has been found to be at least as effective as TAC (tetracaine hydrochloride, adrenaline, cocaine), but with fewer harmful side effects and at a very reduced cost (about 1 / 10 the cost of TAC). Document US5589156A of 05 / 05 / 1995, aerosol compositions used to anesthetize mammals in human and veterinary applications include prilocaine base solubilized in the hydrofluorocarbon (HFC) propellants 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane. Prilocaine base has been found to be readily soluble in HFC propellants when combined in liquid or microrod form, and a solution stable at temperatures as low as -82°C is formed upon combination of the two components. In aerosol compositions,HFCs are the only propellants used. Additional pharmaceutical constituents can also be combined with the prilocaine / HFC base composition to provide a multicomponent anesthetic, and the presence of prilocaine in the combination has been found to aid in the solubilization and / or suspension of these pharmaceutical constituents. Some examples of pharmaceutical compositions in the practice of this invention include HFC, prilocaine base and another pharmaceutical prilocaine selected from the group consisting of bronchodilators, anti-inflammatories, antitussives, vasoactive drugs, vasoconstrictors, antibiotics, peptides, steroids, enzymes, antihistamines, hormones, enzyme and receptor inhibitors and agonists, 5-aminolevulinic acid, antiseptics, disinfectants, procaine, cocaine, chloroprocaine, tetracaine, mepivacaine, lidocaine, bupivacaine, etidocaine, ropivacaine, benzocaine and phenylephrine. Document US20040184999A1 of 01 / 29 / 2004,The present invention relates to the administration of antimigraine compounds through an inhalation route. Specifically, it refers to aerosols containing lidocaine, verapamil, diltiazem, isometheptene, or lisuride that are used in inhalation therapy. In one aspect of the method of the present invention, lidocaine, verapamil, diltiazem, isometheptene, or lisuride are administered to a patient through an inhalation route. The method comprises: a) heating a thin layer of lidocaine, verapamil, diltiazem, isometheptene, or lisuride on a solid support to form a vapor; and b) passing air through the heated vapor to produce aerosol particles containing less than 5% drug handling products. In one kit aspect of the present invention, there is provided a kit for administering lidocaine, verapamil, diltiazem, isometheptene, or lisuride via an inhalation route comprising: a) a thin coating of a composition of lidocaine, verapamil, diltiazem,isometheptene or lisuride and b) a device for dispensing a thin coating referred to as a condensation aerosol. Document No. BR 102013033605-0 of 12 / 27 / 2013 refers to a pharmaceutical composition comprising a mixture of anesthetic and vasoconstrictor salts in an isotonic aqueous solution as a vehicle. The isotonic solution consists of water for injection, saccharin, sodium cyclamate, acesulfame potassium, sodium benzoate, and methylparaben. The anesthetic salts may be: lidocaine hydrochloride, prilocaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, bupivacaine hydrochloride, and articaine, and the vasoconstrictors may be: phenylephrine hydrochloride, epinephrine, norepinephrine, adrenaline, norepinephrine hemitartrate, felypressin, and levonordefrin. This application also relates to the manufacturing process of this pharmaceutical composition in which the addition of anesthetic salts,and vasoconstrictors the modified isotonic aqueous solution is made in the proportion of 1:8, in which the mixture of 3.6 ml of anesthetic salts and vasoconstrictors is added in 0.45 ml of modified isotonic aqueous solution, which was formulated for nasal administration in drops.,

[0045]

[0038] Although the prior art describes intranasal formulations of lidocaine hydrochloride and some approaches use vasoconstrictors and solvents, problems related to low solubility, instability of lidocaine hydrochloride for the desired objective (epilepsy) and, therefore, its impact on bioavailability for optimal therapeutic efficacy continue to be a process of improvement. In addition, optimizing viscosity and pH of formulations for effective intranasal delivery remain a challenge and, therefore, therapeutically effective commercial formulations of lidocaine hydrochloride for the treatment of epilepsy in mammals with these combinations are not available on the market. Furthermore, it would be desirable to offer formulations that enhance the bioavailability of formulations composed of lidocaine, whether free base or hydrochloride, to obtain better therapeutic efficacy.

[0046]

[0039] It is worth noting that intranasal formulations for migraine treatment require another concentration of lidocaine to produce therapeutic effect in relation to the treatment of epilepsy, as well as an in vitro and in vivo model for evaluating absorption and delivery to the nose and brain, for example: in vitro migraine model - Caco-2 cell line, in vitro epilepsy model - Neuro-2a cell line, RAW murine macrophage cell lines (Esim, O.; Savaser, A.; Ozkan, CK; Oztuna, A.; Goksel, BA; Ozler, M.; Tas, C.; Ozkan, Y. Nose-to-brain delivery of eletriptan hydrobromide nanoparticles: Preparation, in vitro / in vivo evaluation and effect on trigeminal activation. J. Drug Deliv. Science. Technology. 2020, 59, 101919) and (Nigam, K.; Kaur, A.; Tyagi, A.; Nematullah, M.; Khan, F.; Gabrani, R.; Dang, S. Nose-to-brain delivery of lamotrigine-loaded PLGA nanoparticles. Damn Deliv. Trans. Res. 2019, 9, 879-890).

[0047]

[0040] All of these prior art treatments use an excessive amount of lidocaine, as there is no consensus on the concentration of lidocaine required to block sodium channels in neurons. A classic study is by Ragsdale et al., published in 1994, where they examined the inhibition of sodium channels by lidocaine and found that the IC50 (50% inhibitory concentration) of lidocaine is in the range of 10 to 100 micromolar (pM). The IC50 is the concentration at which 50% of the sodium channels are blocked. Ragsdale, D.S., McPhee, J.C., Scheuer, T., & Catterall, W.A. (1994). Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science, 265(5179), 1724-1728. Another study that may be useful is: Butterworth, J.F., & Strichartz, G.R. (1990). Molecular mechanisms of local anesthesia: a review. Anesthesiology, 72(4), 711 -734.

[0048]

[0041] The present invention provides new and stable intranasal formulations of lidocaine hydrochloride with optimized concentrations of the drug in its solubilized form and viscosity of the formulation to obtain the desired bioavailability for therapeutic efficacy. Our studies are limited only to epileptic channelopathies in sodium channels; these correlations were only evidenced to demonstrate that it is possible to treat epilepsy via the nasal route, a formulation that we intended to patent, something unprecedented in the state of the art.

[0049]

[0042] In this context, it is important to monitor the growing number of formulations that have been developed, getting closer and closer to what is the “ideal formula”: low MW drugs, high lipophilicity, non-ionized at physiological pH, the most effective treatment regimen, vehicles, absorption promoters and administration devices.

[0050]

[0043] In addition to the present invention presenting a formulation different from the others, it uses another form of administration, since the current nasal administration devices, such as droppers, nasal sprays and atomizers, have some disadvantages that could be updated. Automated inhaler devices, such as dry powder inhalers (DPIs) or assisted devices—metered-dose inhalers, mDIs—are used to deliver solid or liquid dosage forms to the olfactory region of the nasal cavity (Slã, N.; Cleary, M.J. Developing an efficient and reliable dry powder inhaler for pulmonary drug delivery—a review for multidisciplinary researchers. Med. Eng. Phys. 2012, 34, 409-427), (Costantino, R.H.; Ilium, L.; Brandt, G.; Johnson, P.H.; Quay, S.C. Intranasal administration: physicochemical and therapeutic aspects. International J. Pharmaceutics. 2007, 337, 1-24) and (Inthavong, K.; Gé, Q.; Se, C.M.K.; Yang, W.; Tu, JY Simulation of sprayed particle deposition in a human nasal cavity including a nasal spray device. J. Aerosol Sci. 2011 , 42, 100-113).

[0051]

[0044] "drops" or assisted devices - metered dose inhalers (mDIs), administration is justified for the desired objective (epilepsy), as other forms of nasal administration such as spray and nebulization, this factor influences absorption through the IN route is the viscosity of the formulation. At this level, Kundoor and Dalby, through a silicone model representative of the human nose and nasal passages, showed that the deposition area of ​​drug particles administered through a spray whose formulation had a higher viscosity decreases, probably due to an increase in droplet size (Kundoor V, Dalby RN. Effect of Formulation- and Administration-Related Variables on Deposition Pattern of Nasal Spray Pumps Evaluated Using a Nasal Cast. Pharm Res. 2011 ;1895-904.).

[0052]

[0045] The role of intranasal administration devices should also be highlighted, as they influence the efficacy of the medications we intend to administer. Nasal administration methods, such as sprays, tend to have a wide spray angle, and nebulization humidifies the airways, depositing their particles primarily in the respiratory epithelium, which, as already mentioned, is not the most conducive epithelium for the absorption of drugs that act on the brain. Recently, olfactory delivery systems have emerged that deposit the majority of the drug in the olfactory region, which is desirable in order to increase the efficacy of centrally administered medications. (Grassin-delyle S, Buenestado A, Naline E, Faisy C, Blouquit-laye S, Couderc L, et al. Pharmacology & Therapeutics Intranasal drug delivery: An efficient and non-invasive route for systemic administration Focus on opioids. Pharmacol Ther. Elsevier Inc.; 2012;134(3):366-79) - (Hansen MS, Dahl JB.Limited evidence for intranasal fentanyl in the emergency department and the prehospital setting - a systematic review. Dan Med J. 2013;(January):1-6) - (D. Hoekman, John JYHR. Enhanced Analgesic Responses After Preferential Delivery of Morphie and Fentanyl to the Olfactory Epithelium in Rats. Anesth Analg. 2011 ;113(3):641— 51 ).

[0053] INNOVATION OBJECTIVES

[0054]

[0046] NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPSIES IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPTIC CHANNELOPATHY IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE REDUCTION OF EPILEPTIC SEIZURES IN MAMMALS.

[0055]

[0047] The main object of the invention is to provide an intranasal composition of lidocaine hydrochloride for exclusive use in the treatment of epilepsy in mammals.

[0056]

[0048] Another object of the invention is to provide an intranasal composition administered in its solution in drops or assisted devices - metered dose inhalers, (mDIs), applied approximately 0.05ml to 0.20ml or micro drops approximately 0.0166ml to 0.05ml minimum for effect, since the concentration of lidocaine necessary to inhibit sodium channels in nerve axons is in the order of 10 to 100 micromolars (pM).

[0057]

[0049] Another object of the invention is to provide an intranasal composition for use in mammals over 200g.

[0058]

[0050] Another object of the invention is to provide stable, high-concentration formulations for intranasal applications with enhanced bioavailability in drops or assisted devices - metered dose inhalers, (mDIs) of lidocaine hydrochloride to obtain better therapeutic efficacy by the use of targeted penetration boosters.

[0059]

[0051] Another object of the invention is to provide stable, high concentration, clear, transparent solutions of lidocaine hydrochloride in water by using absorption promoters, polymeric substances with mucoadhesive properties that increase the residence time in the nasal mucosa, use of suitable solubilizing agents (cyclodextrins and co-solvents / solubilizers) or mixtures thereof, with or without penetration enhancers to maximize the bioavailability of the drug in intranasal administration.

[0060]

[0052] Another object of the invention is to provide stable, high-concentration solutions for clear, transparent drops of lidocaine hydrochloride in water by using absorption promoters, polymeric substances with mucoadhesive properties that increase the residence time in the nasal mucosa, use of suitable solubilizing agents (cyclodextrins and co-solvents / solubilizers) or mixtures thereof, with or without penetration enhancers, in which the amount of cyclodextrins and co-solvents / solubilizers or mixtures thereof is selected so that the formulation results in enhanced solubility without significantly increasing the viscosity of the intranasal formulation.

[0061]

[0053] Another object of the invention is to provide said stable, high-concentration, transparent clear solutions of lidocaine hydrochloride in lidocaine hydrochloride concentrations ranging from about 1000 mcg / 0.05 ml to about 1,500 mcg / 0.05 ml.

[0062]

[0054] Another object of the invention is to provide said stable, high-concentration, transparent, clear solutions of lidocaine hydrochloride in water having a pH suitable for systemic intranasal delivery of lidocaine hydrochloride medicament ranging from about 6.0 to about 7.0.

[0055] Another object of the invention is to provide said stable, high-concentration, transparent, clear solutions of lidocaine hydrochloride in water having viscosity ranging from about 1 to 100 CPS suitable for systemic intranasal delivery.

[0063]

[0056] Another object of the invention is to provide said stable, high-concentration, transparent clear solutions of lidocaine hydrochloride in water, optionally containing an adequate amount of a mucoadhesive agent or mixtures thereof, which are suitable for systemic intranasal delivery of the drug.

[0064]

[0057] Another object of the invention is to provide said transparent clear solutions of high concentration of lidocaine hydrochloride in water, with or without penetration enhancers such as bile salts, vitamin E TPGS, alkyl maltosides or mixtures thereof, which are suitable for systemic intranasal delivery of the drug.

[0065]

[0058] Another object of the invention is to provide said stable, high-concentration, transparent clear solutions of lidocaine hydrochloride in water, in combination with an adequate amount of chelating agents such as disodium or tetrasodium EDTA in cases of formulations with a pH greater than 7, which are suitable for systemic intranasal release of the drug.

[0066]

[0059] Another object of the invention is to provide said stable, high-concentration, transparent clear solutions of lidocaine hydrochloride in water, in combination with suitable preservatives and antioxidants.

[0067] INNOVATION SUMMARY

[0068]

[0060] NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPSIES IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPTIC CHANNELOPATHY IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE REDUCTION OF EPILEPTIC SEIZURES IN MAMMALS.

[0069]

[0061] The invention patent refers to the intranasal composition of lidocaine hydrochloride associated with pharmacologically acceptable components in a portion of 1 ml to 1.8 ml of a clear, transparent, high-concentration and stable solution, in concentrations of lidocaine hydrochloride ranging from about 1000 mcg / 0.05 ml to about 1,500 mcg / 0.05 ml per drop, with a pH ranging from about 6.0 to about 7.0 and its viscosity ranging from about 1 to 100 CPS, a combination suitable for systemic intranasal release, administered in drops or assisted devices - metered dose inhalers, mDIs about (0.05 ml to 0.20 ml = 1 to 4 drops) or (micro drops about 0.0166 ml to 0.05 ml = 1 to 3 micro drops) minimum necessary for therapeutic effect, its use is recommended for mammals over 200g.

[0070] DESCRIPTION OF FIGURES

[0071]

[0062] NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPSY IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPTIC CHANNELOPATHY IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE REDUCTION OF EPILEPTIC SEIZURES IN MAMMALS, the subject of this invention patent application, will have its formulation described in detail with reference to the drawings listed below, in which:

[0072] Figure 1 Illustrates line graph 1 showing the calibration curve for determining the concentration of lidocaine hydrochloride in the sample from the corresponding peak area;

[0073] Figure 2 illustrates graph 2 of Viscosity vs. Temperature which shows the variation of viscosity with temperature; Figure 3 illustrates graph 3 which shows the variation of viscosity between 1 CPS and 100 CPS over an arbitrary unit of time;

[0074] Figure 4 illustrates Graph 4 of Change in Transepithelial Resistance (Rt) (Q cm 2 ) for the dose of 1,500 mcg;

[0075] Figure 5 illustrates Graph 5 of Change in Transepithelial Resistance (Rt) (Q cm 2 ) for the adjusted dose of 1000 mcg;

[0076] Figure 6 illustrates Graph 6 of Change in transepithelial potential (Vte) (mV) for the 1,500 mcg dose;

[0077] Figure 7 illustrates Graph 7 of Change in short-circuit current (Isc) (pA / cm 2 ) for the dose of 1,500 mcg;

[0078] Figure 8 illustrates Graph 8 of Change in Transepithelial Resistance (Rt) (Q cm 2) for the 1,500 mcg dose of test D without the penetration booster and test E with the penetration booster;

[0079] Figure 9 shows the EEG on admission during status epilepticus showing extremely long interictal suppression and ictal burst activity. The pattern alternated: the first lasted 1 to 2 minutes and the second lasted 15 to 30 seconds;

[0080] Figure 10 shows the EEG recorded 3 days after starting intravenous lidocaine administration showing a typical burst pattern of interictal suppression. B: The EEG recorded 1 month after starting lidocaine therapy shows an irregular slow-wave pattern with a burst tendency.

[0081] DETAILED DESCRIPTION OF THE INNOVATION

[0082]

[0063] NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPSIES IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPTIC CHANNELOPATHY IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE REDUCTION OF EPILEPTIC SEIZURES IN MAMMALS.

[0083]

[0064] The present invention provides formulations for intranasal release, comprising lidocaine hydrochloride, phenylephrine hydrochloride, dissolved in water by the use of absorption promoters, polymeric substances with mucoadhesive properties that increase the residence time in the nasal mucosa, use of suitable solubilizing agents cyclodextrins and suitable co-solvents / solubilizers or mixtures thereof and a buffer system optionally with suitable penetration enhancers such as bile salts, or antioxidants or chelating agents or wetting agents or preservatives or fluidizer or combinations thereof. The invention also provides a process for preparing and method for administering the described formulation.

[0084]

[0065] In one embodiment, the present invention provides compositions comprising an effective amount of lidocaine hydrochloride in a concentration of about 20 mg to 25 mg / 1.00 ml to 1000 mcg / 0.05 ml to about 1500 mcg / 0.05 ml per drop. The justification for the concentration of 1000 mcg / 0.05 ml to approximately 1,500 mcg / 0.05 ml per drop derives from the minimum quantity required for the therapeutic effect in mammals above 200g, since according to paragraph 10 of the grounds for innovation I and paragraph 40 of the state of the art, the concentration of lidocaine required to block sodium channels in neurons is in the range of 10 to 100 micromolars (pM), with only one microdrop (approximately 0.0166 ml of the composition) being required for the therapeutic effect, this dosage is increased according to weight.

[0085]

[0066] In another embodiment, the present invention provides new compositions for releasing lidocaine hydrochloride, phenylephrine hydrochloride, dissolved in water by the use of absorption promoters, polymeric substances with mucoadhesive properties that increase the residence time in the nasal mucosa, use of suitable solubilizing agents cyclodextrins and suitable organic co-solvents / solubilizers or mixtures thereof and a buffer system optionally with suitable penetration enhancers such as bile salts and vitamin E TPGS, or antioxidants or chelating or wetting or fluidizing agents or preservatives or combinations thereof.

[0086]

[0067] To develop a stable water-based formulation, it was necessary to compare which type of lidocaine would be more soluble in water, lidocaine in its free base form: its solubility in water is low, about 0.004 g / mL (4 mg / mL). Transforming the molecule into a salt helps to increase solubility.

[0087]

[0068] Thus, lidocaine hydrochloride has a higher solubility, approximately 0.68 g / mL, but the free base form has greater permeation but lower solubility. On the contrary, the hydrochloride form, despite permeating less, resulting in a lower analgesic effect, its characteristics make it easier to handle in larger doses, solubilize and incorporate into formulations. Another characteristic of lidocaine hydrochloride in relation to the free base form is viscosity. Lidocaine hydrochloride is more viscous.

[0088]

[0069] Lidocaine hydrochloride whose molecular formula is C14H22N2O, having its atomic mass unit or Dalton, between 234 and 288 Da; LogP = 2.4; pH = 6.79 and pKa = 7.8, being chemically designated as alpha-dithelia-amino-2,6-acetoxylidide hydrochloride, has as relevance its physicochemical properties, Molecular Weight, pKa, Partition Coefficient and Protein Binding (%). Relevant characteristics according to paragraphs 33 and 35 of the foundations of innovation II.

[0089]

[0070] Lidocaine hydrochloride has greater solubility in water than in free base form and lower permeation, requiring larger doses to provide the same therapeutic effect compared to the base form, being necessary to equate the quantities for the same permeability effect, since this balance was only achieved with the association of a sympathomimetic (vasoconstrictor) agent Phenylephrine between 0.0003 to 0.0005g / 1.00ml. To provide optimized therapeutic benefit via the nasal route, it is necessary to solubilize Lidocaine hydrochloride from 20mg to 25mg / 1.00ml in such a way that the solutions have a concentration ranging from approximately 1000 mcg / 0.05ml to approximately 1,500 mcg / 0.05ml per drop.

[0090]

[0071] An alternative that has currently been shown to be capable of promoting solubilization are Cyclodextrins (CDs) cyclic oligosaccharides, more specifically modified cyclodextrins. Examples of these synthetic derivatives of natural cyclodextrins include 2-hydroxypropyl-b-CD (HP-b-CD, 2,6-dimethyl-b-cyclodextrin and b-cyclodextrin sulfobutyl ether (Matioli, G.; Cyclodextrins and their applications in: food, pharmaceuticals, cosmetics, agriculture, biotechnology, analytical chemistry and general products, Ed. UEM: Maringá, 2000) and (Rajewski, RA; Stella, VJ; J. Pharm. Sci. 1996, 85, 1142.).

[0091]

[0072] In addition to changes in the properties of these drugs, such as increased solubility and modifications in the release profile, such changes are important for the applicability of these compounds and may lead to improvements in their biodistribution. The article - Repair and physicochemical characterization of inclusion complexes between local anesthetics and hydroxypropyl-beta-cyclodextrin presents physicochemical characterization data on the complexation of two local anesthetics, widely used in clinical medicine, with HP-b-CD. The results indicate that the complexation of local anesthetics causes changes in the properties of these drugs, such as increased solubility and modifications in the release profile. Such changes are important for the applicability of these compounds and may lead to improvements in their biodistribution. In the interaction of local anesthetics with HP-b-CD, it was shown that the ionization state of the drug and its hydrophobicity are decisive.The results also indicate that the drug release profile is differentiated and that the complexation is not strong enough to prevent the release of the anesthetic; instead, the stability constant values ​​are relatively low, which guarantees the release of the drug, but at a slower rate, (https: / / www.scielo.br / j / qn / a / 3jFFknFTjHgQnPL8WcknFDz / ?lang=pt#).

[0092]

[0073] As is generally known, there are numerous degrees of nasal drug preparations, such as “Nasal preparations with successful therapeutic action on the brain - review of clinical pharmacokinetic data - Rita Daniela Beirão dos Santos, Report for obtaining the Degree of Master in Pharmaceutical Sciences” and “UNIVERSITY OF SÃO PAULO SCHOOL OF PHARMACEUTICAL SCIENCES - Undergraduate Course in Pharmacy-Biochemistry - INHALATION THERAPIES: history, technological advances and perspectives - Julia Brediks Prada Final Work of the Pharmacy-Biochemistry Course of the School of Pharmaceutical Sciences of the University of São Paulo”.

[0093]

[0074] These studies contributed to the development of the formulation of the present innovation, where a solubilization / absorption system, buffer system in the combination of pharmacologically acceptable excipients was possible concentrations of lidocaine hydrochloride ranging from about 1000 mcg / 0.05 ml to about 1,500 mcg / 0.05 ml, with a pH ranging from about 6.0 to about 7.0 and viscosity ranging from about 1 to 100 CPS, a combination suitable for systemic intranasal release.

[0094] COMBINED SOLUBILITY AND ABSORPTION SYSTEM

[0095]

[0075] The solvent / absorption system in the combination between HP-b-CD and co-solvents / solubilizers for solubilization and absorption suitable for the concentration intended to be patented, that is, 1000 mcg / 0.05 ml to approximately 1,500 mcg / 0.05 ml per drop of lidocaine hydrochloride.

[0096] Preparation of HP-b-CD-Lidocaine Hydrochloride Complex

[0097] 1. Cyclodextrin (HP-b-CD): Initial cyclodextrin concentration: 10% (m / v).

[0098] 2. Lidocaine hydrochloride: Lidocaine hydrochloride was added to the HP-b-CD solution in a molar ratio of 1:1 or 1:2 (lidocaine hydrochloride), depending on the solubility of lidocaine hydrochloride. Practical Example: Dissolve 10 g of HP-b-CD in 100 ml of water, then add the drug to the HP-b-CD solution (1 mmol of lidocaine hydrochloride to 1 mmol of HP-b-CD), and stir the mixture for 24 hours at room temperature. Different molar ratios of lidocaine hydrochloride, such as 1:1.5 or 1:2, were also tried to see if there was an improvement in solubility.

[0099] Preparation of Solution with Glycofurol

[0100] 3. Glycofurol: initial glycofurol concentration of 10% (v / v).

[0101] The glycofurol concentration was also adjusted to 15% or 20% (v / v) and the experiments were repeated to analyze which solubility was more satisfactory.

[0102] Note: The 10% (v / v) amount of glycofurol was sufficient to significantly improve the solubility of lidocaine hydrochloride without causing instability or precipitation in many cases.

[0103] Practical Example: After the HP-b-CD-lidocaine hydrochloride complex has formed, dissolve the complex in a solution containing 10% (v / v) glycofurol in water. Stir the mixture until the complex is completely dissolved.

[0104] Assessment 1: The solubility of lidocaine hydrochloride in the final solution was measured using a spectrophotometer.

[0105] Spectrophotometer: A series of standard solutions of lidocaine hydrochloride at different known concentrations (e.g., 10, 20, 50, 100, 200 pg / mL) were prepared in an appropriate solvent. Then, a sample containing the HP-b-CD - lidocaine hydrochloride complex dissolved in glycofurol was prepared.

[0106] Spectrophotometer Setup: The spectrophotometer was turned on and allowed to warm up for about 15-30 minutes, then the wavelength of 250 nm was selected.

[0107] Absorbance Measurement: Each standard solution was placed in a cuvette and the absorbance measured at a wavelength of 250 nm. The same was done with the sample containing the HP-b-CD complex - lidocaine hydrochloride dissolved in glycofurol.

[0108] Calibration Curve: The absorbance of the standard solutions was plotted as a function of their concentrations, then the best fit line was drawn to create the calibration curve.

[0109] Determination of Sample Concentration: The calibration curve was used to determine the concentration of lidocaine hydrochloride in the sample from its measured absorbance.

[0110] Absorbances of Standard Solutions: o 10 pg / mL Abs = 0.1 o 20 pg / mL Abs = 0.2 o 50 pg / mL Abs = 0.5 o 100 pg / mL Abs = 1.0 o 200 pg / mL Abs = 2.0 Sample: Abs = 0.75

[0111] Sample Concentration: Using the calibration curve (Figure 1), the sample concentration was approximately 75 pg / mL. Graph 1, illustrated in Figure 1, shows the calibration curve line used to determine the lidocaine hydrochloride concentration in the sample from the corresponding peak area. The blue line represents the standard solutions, while the red line is the fit line obtained by linear regression. The green dot represents the unknown sample, with a peak area of ​​75,000 and an estimated concentration of approximately 75 pg / mL.

[0112] Evaluation 2: The solubility was compared with that of solutions containing only HP-b-CD and only glycofurol to evaluate the effectiveness of the combined system.

[0113] Stability: The final solution was stored under different temperature conditions and the concentration of lidocaine hydrochloride was measured over time to assess stability.

[0114] Conclusion: This suggested ratio is a reasonable starting point. Based on the initial results, you can adjust the concentrations as needed to optimize drug solubility and absorption.

[0115]

[0076] Based on the above experiment, solubilization can be achieved in the desired concentration range to produce solutions of controlled viscosity, through judicious formulation of a solvent / absorption system: HP-b-CD and co-solvents / solubilizers such as glycofurol and polyethylene glycols or mixtures thereof individually or in combination with water, in which the combination of HP-b-CD and co-solvents / solubilizers are between lidocaine hydrochloride 60% to HP-b-CD 30% and co-solvents / solubilizers 10%. Furthermore, the formulations were optimized in terms of viscosity and pH to ensure maximum intranasal absorption of the drug to obtain therapeutic efficacy and bioavailability with better patient compliance.

[0116]

[0077] In addition to the solvent system, the formulation includes other pharmaceutically acceptable excipients selected from, but not limited to, a group of excipients comprising humectants such as xylitol, and / or preservatives and / or fluidifiers and / or antioxidants and / or penetration enhancers and / or mucoadhesives.

[0117]

[0078] As a fluidifier benzalkonium chloride and preservatives benzoic acid, benzyl alcohol, bronopol, butylated, hydroxyl anisole, butylated hydroxyl toluene, chlorocresol, or isopropyl alcohol or a combination thereof.

[0118]

[0079] The penetration enhancers of the present invention can be selected from bile salts among others. Non-limiting examples of such penetration enhancers are sodium glycocholate, sodium taurocholate, dodecyl maltosides, tridecyl maltosides or tetradecyl maltosides, or a combination thereof. The penetration enhancers are used up to 2.0% by weight of the compositions.

[0119]

[0080] Mucoadhesives are selected from natural polymers such as tragacanth, sodium alginate, karaya gum, guar gum, xanthan gum, lectin, soluble starch, gelatin, pectin and chitosan, and are used up to 5% by weight of the composition.

[0120]

[0081] Humectants are selected from glycerin, sodium lactate, sorbitol, xylitol, butylene glycol.

[0121]

[0082] Surprisingly, we have discovered that it is possible to obtain the desired viscosity of approximately 1 to 100 CPS (centipoise) through a judicious combination of ingredients, especially the solvent system, and still provide significantly increased transnasal absorption of lidocaine hydrochloride. The formulations are presented as a clear, transparent, high-concentration, stable solution, administered in drops or assisted devices - metered dose inhalers (mDIs), their use is monotherapeutic or / and in combinations. It is important to note that despite the lower viscosity of the formulations of the present invention, they did not compromise the transnasal absorption of the drug. The present invention is a distinct departure from the teachings of the prior art and yet achieves a perfect balance between viscosity, ease of absorption, and bioavailability.

[0122]

[0083] When measuring viscosity, it is first important to record the temperature to understand how the composition behaves. Three aliquots of the composition sample were prepared and each placed in a separate container to measure the viscosity at the controlled temperature. For temperature control, a thermostatic bath was used to heat or cool each sample to specific temperatures: 10°C, 25°C, 30°C, and 40°C.

[0123]

[0084] Graph 2 of Viscosity vs. Temperature, (figure 2) shows the variation of viscosity with temperature.

[0124] Interpretation of Graph 2:

[0125] At 10°C: Viscosity is 120 CPS.

[0126] At 15°C: Viscosity drops to 89 CPS.

[0127] At 25°C: Viscosity drops further to 1200 CPS. At 30°C: Viscosity decreases to 1050 CPS.

[0128] At 40°C: Viscosity decreases further to 3 CPS.

[0129] Results: These results show that the viscosity of the nasal composition decreases with increasing temperature, and room temperature (15 - 30°C) is ideal for using the composition.

[0130]

[0085] After the viscosity variation tests with temperature, the viscosity was measured with a Rotational Viscometer, its data were recorded and interpreted as shown in Figure 3, which illustrates graph 3, which shows the variation in viscosity between 1 CPS and 100 CPS over an arbitrary unit of time. The blue line represents the viscosity, while the red and green dotted lines indicate the values ​​of 1 CPS and 100 CPS, respectively, with the ideal viscosity x temperature being approximately ± 12 CPS to ± 90 CPS. References: "Remington: The Science and Practice of Pharmacy" - This is one of the leading reference texts in pharmacy, covering formulations of different types of drugs, including those for nasal administration. "Pharmaceutical Dosage Forms and Drug Delivery Systems" by Ansel, Allen, and Popovich - This book covers various dosage forms, including viscosity requirements for nasal solutions. "Nasal Drug Delivery" by K.J.Kimberlin - This book specifically covers nasal medication formulations, with details on viscosity and other necessary physical properties.

[0131]

[0086] The formulations of the present invention optionally comprise additional pharmaceutically acceptable excipients that are used to further improve the stability of the formulations. Non-limiting examples of such excipients are chelating agents such as sodium EDTA and / or antioxidants that do not irritate the nasal mucosa. A non-limiting example of such antioxidants is ascorbic acid.

[0132]

[0087] Merely achieving solubilization is not a sufficient condition to ensure maximum absorption of a drug containing lidocaine hydrochloride. Parameters such as formulation viscosity and drug stability over shelf life also need to be optimized to ensure the required transnasal absorption and bioavailability for therapeutic efficacy.

[0088] A variety of solutions with pH ranging from approximately 3.75 to 7 were prepared. Suitable buffer systems such as citrate buffer can be used to obtain the desired pH. Therefore, it was necessary to determine the impact of pH on the intranasal absorption of lidocaine hydrochloride.

[0133]

[0089] To evaluate the impact of pH on the intranasal absorption of lidocaine hydrochloride, 2% lidocaine hydrochloride solutions were prepared and bioavailability studies were conducted for the formulations exhibiting pH 3.75, 5 and 6.25. For this purpose it was first necessary to reduce pH (-1), as lidocaine hydrochloride has a pH 7.4 in a mixture with chelating agents such as sodium EDTA, Tetrasodium in the Buffer system 3% of the total value.

[0134]

[0090] We surprisingly found that pH above 6 is more appropriate for obtaining the desired intranasal absorption of lidocaine hydrochloride. The results are provided in Tables 1 & 2 below.

[0135] Tables 1 with a dose of 1,500 mcg and adjusted dose of 1000 mcg with baseline correction: is presented below.

[0136] Tables 2 Process for preparing the compositions:

[0137]

[0091] The said composition is obtained by a basic Production process, Cold Addition, or Simple Mixing of the Components.

[0138] The entire preparation was carried out at room temperature and shaken for a period of 24 hours, then centrifuged for 15 minutes at 20 mg. Dissolved oxygen levels were kept as low as possible, preferably around 1 to 1.5 ppm.

[0139] The process comprises the steps of i) Addition of HP-b-CD and polyethylene glycols at 50% v / v water to the batch; ii) Addition of buffer to the solution using citrate buffer; iii) Addition of Lidocaine Hydrochloride with stirring until dissolved; iv) Addition of Phenylephrine Hydrochloride with stirring until dissolved v) Dissolution of benzalkonium chloride and xylitol with stirring; vi) Adjustment of pH to the required value by addition of acid / alkali; vii) Composition of volume / solution 1.0 ml to 1.8 ml to obtain the desired concentration of 1000 mcg per 0.05 ml of the solution in one drop of Lidocaine Hydrochloride.

[0140]

[0092] The compositions of the present invention would typically comprise: the medicament: 0.02g / 1.00ml; solvents: (total) 45%; humectant: 0-5%; mucoadhesive: up to 5%, penetration enhancers: up to 1.5%; preservatives: up to 4%, with a concentration of about 1,000 mcg / 0.05ml to 1,500 mcg / 0.5ml of Lidocaine Hydrochloride possible in each drop. The compositions, as also described in the specification, would further contain buffering ingredients to adjust the pH to the required value, depending on the medicament used.

[0141] STUDIES ON THE PERMEATION OF NASAL MUCOSA IN USSING CHAMBERS OF THE NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPSY IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPTIC CHANNELOPATHY IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS IN THE REDUCTION OF EPILEPTIC SEIZURES IN MAMMALS.

[0142]

[0093] A nasal mucosal permeation study of the above metered dose inhaler (mDIs)-type device-assisted device containing 1000 mcg / 0.05 ml to about 1500 mcg / 0.05 ml per drop of lidocaine hydrochloride was conducted on mucous membranes of pigs.

[0143]

[0094] For the nasal mucosa permeation study project, an ex vivo clinical trial was conducted in sloughing chambers. The mucosa studied originated from pigs. The pigs used to obtain the nasal mucosa were slaughtered in slaughterhouses. The animals' noses were removed and opened to expose the nasal concha. The mucosa covering the ventral nasal mucosa was removed with the aid of tweezers and scalpels, then placed in vials with KRB and ice. This process took a maximum of 10 minutes. Transport to the laboratory took a maximum of 15 minutes. In some trials, the animal's head was also cut in half and transported in ice and KRB to the laboratory, where the nasal septum mucosa was extracted.

[0144] Of the two types of porcine mucosa described above, it has been proven that the mucosa of the ventral nasal cavity is more suitable for permeation testing than the mucosa of the nasal septum. No treatment was performed on the collected mucosa; it was directly mounted in the chambers. After obtaining the membranes, the buffer solution to be used in the test was chosen. A variety of solutions with pH ranging from approximately 3.75 to 7 were prepared. Suitable buffer systems, such as citrate buffer, can be used to obtain the desired pH. After collecting and treating the mucosa, it was mounted in the slurry chambers, with the mucosa on the donor side and the submucosa on the recipient side. Horizontal chambers with areas of 0.64 cm were used. 2 , in some of these tests in which the mucosa faces the upper chamber and the submucosa faces the lower chamber.

[0145]

[0096] The buffer solution is then inserted into both chambers, with temperature control at 37 Q C and oxygenation of the solution to maintain the viability of the mucous membranes and agitation of the medium.

[0146]

[0097] Pre-incubation before inserting the donor solution. The most commonly used pre-incubation time was 15 min or 60 min for pig mucosae, in permeation tests, with aliquots being collected during the test or only at the end of the test. The total duration of the test was 180 min. Mucosal viability was controlled by measuring electrophysiological parameters, including transepithelial potential (Vte), short-circuit current (Isc), and transepithelial resistance (Rt).

[0147] -Tests with oxygenation: 55%

[0148] • Tests at 37°C Q C: 75%

[0149] • Pre-incubation time: o 15 min: 20 % o 30 min:

[0150] • Interval between collections: 15 min: 25% or 30 min: 25%

[0151] • Total test time: 180 min: 15%

[0152] Study Product: (Formula described in Table 1)

[0153] Test Product (A): Lidocaine Hydrochloride with a dose of 1,500 mcg / 0.5 ml adjusted to 1,000 mcg / 0.5 ml

[0154] Test Product (B): Lidocaine Hydrochloride with a dose of 1,500 mcg / 0.5 ml adjusted to 1,000 mcg / 0.5 ml

[0155] Test Product (C): Lidocaine Hydrochloride with a dose of 1,500 mcg / 0.5 ml adjusted to 1,000 mcg / 0.5 ml

[0156] Test Conducting

[0157] Objective: To evaluate the impact of the new composition on the permeability of the nasal epithelium.

[0158] Initial Stabilization - Equilibrium: The chamber was allowed to equilibrate for approximately 30 minutes to 1 hour for tissue stabilization. Monitoring: Measuring electrodes were used to measure parameters and record baseline values ​​of transepithelial potential (Vte), short-circuit current (Isc), and transepithelial resistance (Rt). These electrodes were connected to amplifiers to amplify the weak electrical signals from the electrodes. An Analog-to-Digital Converter (ADC) converted the analog signals from the amplifiers into digital data processed by the data acquisition software, uSsng (Warner Instruments).

[0159] Medication Application - Initial Control: Baseline values ​​were recorded for comparison from 30 minutes to 1 hour, where the tissues are equilibrizing under the experimental conditions.

[0160] Composition Addition: 0.20 ml of Test Product (A), (B), and (C) were aspirated (one at a time) into the apical solution using a 1 ml syringe (without the needle) in the apical (mucosal) compartment of the chamber. The composition was added slowly and in a controlled manner to avoid the formation of air bubbles and ensure that it was distributed evenly and without disturbing the tissue. The 0.20 ml volume added was sufficient to completely cover the tissue surface without causing overflow, and after addition of the composition, the system reached equilibrium in ± 12 minutes. Exposure Time: Tissue responses were monitored and recorded over a specified period (180 min).

[0161] Data Collection: During the baseline period, data were collected at regular intervals. Values ​​were recorded every minute for 30 minutes, with the following simulated transepithelial resistance (Rt) data:

[0098] The baseline was calculated to represent the average value of transepithelial resistance under steady-state conditions prior to application of the composition.

[0162]

[0099] This value was used as a reference to compare changes in parameters after application of the composition, helping to identify and quantify the effects of the treatment.

[0163] Measured Parameters: Continuously record Vte, Isc, and Rt using the uSsng data acquisition system (Warner Instruments).

[0164] Data Analysis: This study was conducted for the 1,500 mcg dose of lidocaine hydrochloride, and statistical analysis was performed for the 1,500 mcg dose as well as for the adjusted 1,000 mcg dose. The mean plasma concentration-time profile for the 1,500 mcg dose is shown in Figure 2, and the mean plasma concentration-time profile for the single-dose 1,000 mcg adjusted data is shown in Figure 3. The mean area in the nasal epithelium permeability under transepithelial resistance (Rt) (Q cm 2 ) for the 1,500 mcg and 1,000 mcg dose of the test formulations are listed in Table 2.

[0165] Results: transepithelial resistance - Rt (Q cm 2 ) for Lidocaine Hydrochloride at a dose of 1,500 mcg and adjusted dose of 1,000 mcg with baseline correction: is presented below.

[0166] Tables 3

[0167]

[0100] The results of the bioavailability studies of the three formulations of the change in transepithelial resistance (Rt) between the control group and the post-treatment group show that test “A” with a dose of 1,500 mcg provided the maximum transnasal release of Lidocaine Hydrochloride. It is noteworthy that the availability of Lidocaine Hydrochloride increased dramatically by increasing the pH from 3.75 to 6.25. The graphs for the 1,500 mcg dose as well as the graphs for the adjusted dose of 1000 mcg are provided in Figure 4 and Figure 5.

[0168]

[0101] Surprisingly, the pH range for favorable absorption of Lidocaine Hydrochloride was 5-7 with the most preferred pH being 5.5 to 7, with pH 6.25 being most suitable for the highest absorption. It may be noted that pH values ​​above 7 are not preferred since high pH facilitates the development of pathogenic bacteria in the nasal passage.

[0169] Graphs and Tables

[0170] Table 4: Baseline and Post-Treatment Electrophysiological Parameters of Test Product (A), (B), and (C)

[0171] 'Values ​​expressed as mean ± standard deviation. *P < 0.05 compared to control.

[0172] Description of Results

[0173] 'Test “A” with a dose of 1,500 mcg and a pH of 6.25

[0174] - Vte: The transepithelial potential (Vte) showed a slight reduction after application of the composition, but it was not statistically significant.

[0175] Interpretation of Graph 6 (Figure 6)

[0176] Control: The mean transepithelial potential is -3.2 mV with a standard deviation of 0.5. Post-Treatment: The mean transepithelial potential after application of the composition is -2.8 mV with a standard deviation of 0.4.

[0177] Significance: The small change in transepithelial potential suggests a change in the electrical potential difference across the nasal epithelium after application. Although this change is not very large, it may indicate a slight modulation of the epithelial barrier by the drug.

[0178] - Isc: The short-circuit current (Isc) increased slightly, indicating an increase in the electrogenic activity of the epithelium, although it was not statistically significant.

[0179] Interpretation of Graph 7 (Figure 7)

[0180] Control: The average short-circuit current is 18.4 pA / cm 2 with a standard deviation of 1.2.

[0181] Post-Treatment: The average short-circuit current after application of the composition is 20.1 pA / cm 2 with a standard deviation of 1.3.

[0182] Significance: Increased short-circuit current after treatment suggests increased electrogenic activity of the nasal epithelium, possibly indicating an effect of the composition on ionic transport across the epithelium.

[0183] - Rt: Transepithelial resistance (Rt) indicates an increase in the permeability of the nasal epithelium when its resistance decreases significantly after application of the composition, this decrease can reach up to 85.4 Q cm 2 , because in our experiments, we noticed that below (80.2 Q cm 2 ), also decreases the permeability of the nasal epithelium.

[0184] Interpretation of Graphs 4 and 5 (Figures 4 and 5)

[0185] Control: The mean transepithelial resistance is 125.3 Q cm 2 with a standard deviation of 5.4.

[0186] Post-Treatment: The average transepithelial resistance after application of the composition is 95.6 Q cm 2 with a standard deviation of 4.8.

[0187] Significance: The significant decrease in transepithelial resistance after application of the composition suggests an increase in the permeability of the nasal epithelium due to the drug.

[0102] It was further surprising that the addition of penetration enhancers such as bile salts, Non-limiting examples of these penetration enhancers are sodium glycocholate, sodium taurocholate, dodecyl maltosides, tridecyl maltosides or tetradecyl maltosides or any combination thereof, significantly impact the absorption and bioavailability of Lidocaine Hydrochloride when the formulation is delivered nasally. Therefore, the Lidocaine Hydrochloride formulation without the penetration enhancer (Test D) was compared with a Lidocaine Hydrochloride formulation with 1.5% penetration enhancer (Test E) to evaluate the effect of the penetration enhancer (Test E) on the intranasal absorption of Lidocaine Hydrochloride. The pH of these formulations was adjusted to 6.25 ± 0.25.The composition of these test formulations is described in the table below. Please also see Figure 7.

[0188] Tables 5

[0189] Tables 6

[0190]

[0103] The results surprisingly show that the transnasal penetration of Lidocaine Hydrochloride was significantly increased in the presence of a small amount of the penetration enhancer. Since higher concentrations of sodium taurocholate have been shown to cause nasal irritation, the concentration of sodium taurocholate was preferably adjusted to a maximum of 1.5% w / v of the formulations.

[0191] Interpretation of Graph 8 (Figure 8)

[0192] Control: The mean transepithelial resistance is 125.3 Q cm 2 with a standard deviation of 5.4.

[0193] Post-Treatment: The mean transepithelial resistance after application of the composition is 88.5 ± 3.8 Q cm 2 with a standard deviation of 4.8.

[0194] Significance: A significant decrease of 95.6 ± 4.8 Q cm 2 (test A) for 88.5 ± 3.8 Q cm 2 (Test E) on transepithelial resistance after application of the composition shows an increase in nasal epithelial permeability due to enhanced penetration. This significant reduction in transepithelial resistance (Rt) suggests that the composition increases nasal epithelial permeability, possibly by modulating tight junctions.

[0195] Conclusions

[0196] Summary: The results showed that the “E” test with a dose of 1,500 mcg in the presence of a small amount of the penetration booster, with a pH of 6.25 the most suitable for the highest absorption, its viscosity around ± 12 to ± 90 CPS (centipoise) through a judicious combination of the ingredients, facilitates absorption and bioavailability, which provides an increase in the permeability of the nasal epithelium of Lidocaine Hydrochloride.

[0197] Clinical Implications: Increasing the permeability of the nasal epithelium may be beneficial in improving the delivery of Lidocaine Hydrochloride through the nasal mucosa under normal conditions to its target of action.

[0198] Next Steps: We suggest next steps for future research, including in vivo studies or clinical trials.

[0199] POSSIBLE PROOF OF THE EFFICACY OF “NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPSY IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPTIC CHANNELOPATHY IN MAMMALS, NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS IN THE REDUCTION OF EPILEPTIC SEIZURES IN MAMMALS”

[0200]

[0104] There are studies that point to a relationship between migraine and epilepsy. References: Silberstein, SD, & Dodick, DW (2013). Migraine and epilepsy: overlapping disorders or coincidental comorbidities?. This article reviews the overlap between migraine and epilepsy, discussing possible common mechanisms and management strategies.

[0201] References: Parisi, P., & Striano, P. (2018). “The Epilepsy-Migraine Connection”. This study explores the connection between epilepsy and migraine, including clinical and therapeutic aspects.

[0202] References: Rajapakse, T., & Pringsheim, T. (2016). "Comorbidities of Migraine: A Systematic Review and Meta-Analysis". This meta-analysis examines the prevalence of comorbidities, including epilepsy, in patients with migraine.

[0203] References: Pellesi, L., Guerzoni, S., Pini, LA, & Cainazzo, MM (2018). "Migraine and epilepsy: Potential therapeutic targets from pathophysiology overlap.". This article discusses potential therapeutic targets based on the pathophysiological overlap between migraine and epilepsy.

[0105] The link between migraine and epilepsy appears to be based not only on common genetics, but, more importantly, on a shared pathophysiological mechanism. Both pathologies can be classified as channelopathies, an emerging and only recently delineated group of neurological disorders. As highlighted in red in Table 7 above.

[0204]

[0106] Cites in the state of the art document no. BR 102013033605-0 of 12 / 27 / 2013, more specifically in its technical opinion published in RPI no. 2622 of 04 / 06 / 2021, points out some prior use of lidocaine in nasal use, for example the study published in Maizels M., et al. JAMA, vol. 276(4), p. 319-321 of 1996 demonstrates that the use of intranasal lidocaine for the treatment of migraine promotes pain relief in approximately 55% of patients, this is just one of many studies that uses intranasal lidocaine for migraine relief.

[0205]

[0107] The state of the art also cites numerous epilepsy treatments using lidocaine, free base or hydrochloride for the treatment of epilepsy.

[0206]

[0108] Logically speaking, if intranasal lidocaine can provide pain relief for approximately 55% of migraine patients, it may also produce some systemic effect on epileptic seizures, as migraine and epilepsy are highly prevalent paroxysmal syndromes. Some of their varied clinical manifestations can be classified as neuronal channelopathies, a group of neurological disorders caused by alterations in ion channels. Migraine and epilepsy are recurrent disorders with paroxysmal manifestations due to changes in brain excitability.

[0207]

[0109] Another study that cites epileptic channelopathies as an epilepsy problem and the efficiency of lidocaine use for its treatment is LIDOCAINE-DEPENDENT EARLY INFANTILE STATUS EPILEPTICUS WITH HIGHLY SUPPRESSED EEG. (https: / / doi.orq / 10.1046 / 1.1528-1157.2002.25301 .x). Abstract: We report an early infantile patient characterized by intractable hyponatremia, progressive megaencephaly, and epileptic seizures with an EEG pattern alternating between interictal low-voltage background and ictal burst activity. All abnormal findings repeatedly improved in a lidocaine-dependent manner. Given the pharmacological mechanisms of lidocaine as a sodium channel blocker, we speculate that our patient had sodium channel dysfunction. The EEG showed burst activity during the convulsive movements and low-voltage activity during the interictal phase lasting 1 to 2 min (Figure 9).Three days after starting lidocaine, she was able to breastfeed, and the duration of the low activity phase on the EEG decreased to <10 s (Figure 10).

[0208]

[0110] Based on the above paragraphs 108 and 109, and in combination with paragraph 10 of the fundamentals of innovation I and paragraph 40 of the state of the art, and according to the characteristics of the composition that follows all the requirements as revealed by the fundamentals of innovation II, and because they are presented in the form of a clear transparent solution of high concentration and desirable stability, administered in drops or assisted devices - metered dose inhalers, mDIs approximately (0.05ml to 0.20ml = 1 to 4 drops) or (micro drops approximately 0.0166ml to 0.05ml = 1 to 3 micro drops) for monotherapeutic use or / in combinations, it is obvious that the present composition will also have been effective in the treatment of epilepsies, epileptic channelopathies (sodium channel dysfunction) and epileptic seizures in mammals over 200g.

[0209]

[0111] Observations: According to the fundamentals of innovation I, in paragraph 3 in combination with table 7, it reveals epileptic channelopathies in potassium and calcium channels, and, since Lidocaine Hydrochloride in low concentrations has vasodilatory properties, which increases its systemic absorption, it has the ability to block fast sodium channels in the following situations: reduced pH, fast stimulation rates, increased extracellular potassium concentrations, reduced potassium and reduced membrane potential, increasing the depolarization threshold, slightly depressing phase 0 of depolarization and may shorten the duration of the action potential, and; inhibiting the excitability of excitatory amino acids. Lidocaine Hydrochloride can increase refractoriness in partially depolarized fibers, reducing intracellular sodium activity and the magnitude of transient inward currents responsible for some forms of afterpotentials.Intracellular calcium activity can be reduced by the calcium-sodium exchange mechanism. Lidocaine Hydrochloride has properties to control status epilepticus when refractory to other treatments due to its mechanism of action. (https: / / www.cristalia.com.br / arquivos_medicamentos / 183 / Package Insert.

[0210] _Xylestsin_lsobarico_2_sol.inj_PS.pdf) and https: / / www.revportcardiol.org / pt- canalopaties-cardiacas-o-papel-das-articulo-S0870255117302688.

[0211]

[0112] Conclusion: As Lidocaine Hydrochloride in low concentrations can reduce potassium and intracellular calcium activity through the calcium-sodium exchange mechanism, we believe that the NASAL COMPOSITION COMPOSED OF LIDOCAINE HYDROCHLORIDE IN MONOTHERAPEUTIC USE OR / IN COMBINATIONS FOR THE TREATMENT OF EPILEPSIES, EPILEPTIC CHANNELOPATHY and in the REDUCTION OF EPILEPTIC SEIZURES IN MAMMALS”, also has some therapeutic effect on potassium and calcium channels.

[0212]

[0113] Final Note: The entire theoretical part was developed by the inventors and the entire laboratory part was financed by ArtOdonto - Specialized Dentistry LTDA. The responsible observer for the tests was Dr. Edvaldo Martins, registered with CROES no. 1550 with specialties in micromolar anesthesia (pM) and prevention of anesthesia application in patients with epilepsy.

Claims

MODIFIED CLAIMS Received by the International Bureau on December 31, 2024 (31.12.2024)

1. NASAL COMPOSITION OF LIDOCAINE HYDROCHLORIDE FOR THE TREATMENT OF EPILEPSY, administered in drops or assisted devices - metered dose inhalers, being composed of an active constituent, sympathomimetic agent, absorption promoter, solvent and auxiliary material, which is characterized by the fact that the active constituent includes lidocaine hydrochloride, and as sympathomimetic agent phenylephrine, the absorption promoter hydroxypropyl-P-cyclodextrin and as solvent polyethylene glycols; The auxiliary material includes Benzalkonium Chloride as a Fluidizer with preservative function, as humectants Xylitol, the penetration enhancer Sodium Taurocholate, the buffering agent Sodium Citrate dihydrate, the chelating agent Tetrasodium and as mucoadhesives sodium alginate; Wherein, the concentration of the active constituent, sympathomimetic agent, absorption promoter, solvent and auxiliary material, is in relation to the total mass of the composition in water qs to 1.0 ml and pH adjusted to 6.28; Claim 2] NASAL COMPOSITION OF LIDOCAINE HYDROCHLORIDE FOR THE TREATMENT OF EPILEPSY, according to claim 1, characterized in that it consists of an active constituent that includes lidocaine hydrochloride; Where, the mass concentration of lidocaine hydrochloride is 2% by weight; The mass concentration of Phenylephrine Hydrochloride is 0.04-0.05% by weight; The mass concentration of Benzalkonium Chloride is 0.08-0.085% by weight; The mass concentration of Xylitol Hydrochloride is 8-9% by weight; The mass concentration of the Combination of hydroxypropyl-P-cyclodextrin and polyethylene glycols is 4% by weight; The mass concentration of Sodium Taurocholate is 0.10-0.15% by weight; The mass concentration of the Combination of Sodium Citrate Dihydrate and Tetrasodium Citrate is 1.20-1.28% by weight; MODIFIED SHEET (ARTICLE 19) The mass concentration of Sodium Alginate is 5% by weight. MODIFIED SHEET (ARTICLE 19)

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