Non-pungent derivatives of capsaicin for the treatment of brain injury resulting from reduced cerebral blood flow

Abstract

The present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable vehicle and non-pungent derivatives of capsaicin, in their tautomeric forms and pharmaceutically acceptable salts, as the sole active ingredient, for use in the stimulation of the sphenopalatine ganglion and the enhancement of cerebral blood flow, to prevent or reduce brain injury resulting from decreased cerebral blood flow. The composition is administered via the oral transmucosal route, preferably in the form of a mucoadhesive tablet, and may be formulated for immediate or prolonged release, ensuring effective and tolerable absorption while avoiding the irritant effects associated with pungent capsaicin.

Description

[0001] NON-PUNGENT CAPSAICIN DERIVATIVES FOR THE TREATMENT OF CEREBRAL BLOOD FLOW REDUCTION INJURY: COMPOSITION AND METHOD OF ADMINISTRATION WITHOUT IRRITANT EFFECTS FIELD OF THE INVENTION

[0002] The present invention relates to increasing cerebral blood flow through intraoral transmucosal chemical stimulation of the sphenopalatine ganglion, using non-pungent capsaicin derivatives. Specifically, the invention is aimed at treating vascular neurological diseases associated with decreased cerebral blood flow, avoiding the irritating effects and burning sensation characteristic of pungent compounds, thus allowing for greater tolerability and therapeutic adherence in patients.

[0003] BACKGROUND OF THE INVENTION

[0004] Vascular neurological diseases resulting from decreased cerebral blood flow include serious medical conditions such as stroke, vasospasm secondary to subarachnoid hemorrhage, and vascular dementia (Ahad, Kumaran et al. 2020). Despite advances in the prevention and treatment of these diseases, they remain the leading cause of disability and the second leading cause of death worldwide (Chauhan, Gaidhane et al. 2024). Brain damage caused by decreased cerebral blood flow can be limited by evidence-based treatments that restore cerebral blood flow as quickly as possible. However, time is a critical factor, as brain tissue becomes irreversibly damaged over time (Powers, Derdeyn et al. 2015).

[0005] Since 1996, intravenous thrombolysis with tissue plasminogen activator (tPA) has been an effective therapeutic option, although its application window is limited (4.5 hours) and its success rate in restoring flow is only 30%. In 2015, mechanical thrombectomy, a technique that allows the direct removal of vascular occlusions, showed a higher success rate in restoring flow (80%) and better functional outcomes when applied within the first 6 hours of symptom onset (Goyal, Tsivgoulis et al. 2019). However, more than 50% of patients do not regain functional independence, mainly due to irreversible damage that occurred before the intervention (Ghozy, Kacimi et al. 2022).

[0006] Therefore, it has been proposed that one way to improve clinical outcomes is through interventions that increase cerebral blood flow early, thereby reducing tissue damage while restoring main flow (Yadollahikhales, Borhani-Haghighi et al. 2016).

[0007] Among these interventions, stimulation of the sphenopalatine ganglion using electrical, magnetic, or chemical stimulation has been shown to be effective in producing cerebral vasodilation and increasing blood flow (Marquez-Romero and Sanchez-Ramirez 2024). However, electrical and magnetic stimulation techniques have significant limitations, such as dependence on electronic devices, highly trained personnel, prolonged application time, and limited availability of specialized equipment.

[0008] A previously granted patent entitled "CAPSAICIN AND / OR CAPSAICIN DERIVATIVES FOR USE IN THE TREATMENT OF DAMAGE RESULTING FROM DECREASED CEREBRAL BLOOD FLOW" described the use of capsaicin and / or its pungent derivatives for intraoral transmucosal chemical stimulation of the sphenopalatine ganglion, achieving a significant increase in cerebral blood flow. However, given its pungent nature, the use of capsaicin is associated with an intense burning sensation and irritation, which may limit its acceptance, tolerance, and widespread use in patients.

[0009] In this context, the present invention proposes a significant improvement by using non-pungent capsaicin derivatives for intraoral transmucosal chemical stimulation of the sphenopalatine ganglion, eliminating irritant effects and ensuring greater patient comfort and safety. This innovation aims to maintain therapeutic efficacy in increasing cerebral blood flow while improving tolerability and adherence to treatment, allowing for broader and safer application in the management of vascular neurological diseases.

[0010] BRIEF DESCRIPTION OF THE INVENTION

[0011] Capsaicin and its derivatives have been shown to stimulate the sphenopalatine ganglion and, as a result, increase cerebral blood flow when administered orally via transmucosal injection. However, the use of capsaicin and pungent derivatives is associated with an intense burning sensation and irritation, which limits their tolerability and clinical application in patients with neurovascular diseases.

[0012] Therefore, the present invention is directed to pharmacological compositions containing a pharmaceutically acceptable vehicle and non-pungent capsaicin derivatives, composed of the following general formula (I):

[0013] R - C6Í¡4- NHCO - (CH2) n - R'

[0014] Where:

[0015] • R: Represents a hydroxyl group (-OH), methoxyl group (-OCH3), or a combination of both at specific positions (such as positions 3 and 4) on the aromatic ring. These groups modify the affinity for the TRPV1 receptor, reducing pungency.

[0016] • NHCO: Amide group that connects the aromatic ring to the alkyl chain.

[0017] • (CH2)n: A linear hydrocarbon chain, where n can vary between 7 and 9. This length balances solubility and transmucosal absorption.R': Hydrophobic terminal group (-CH3, -CH2CH3, -OCH3), which influences the interaction with receptors and the solubility of the molecule.

[0018] in its tautomeric forms and pharmacologically acceptable salts, as the sole active ingredient, to produce intraoral transmucosal chemical stimulation of the sphenopalatine ganglion and thereby increase cerebral blood flow effectively and without causing irritating effects.

[0019] This invention also relates to the use of non-pungent capsaicin derivatives, as mentioned above, as the sole active ingredient in the manufacture of pharmaceutical compounds intended to stimulate the sphenopalatine ganglion and increase cerebral blood flow through transmucosal oral administration, ensuring better tolerability and comfort for the patient.

[0020] Furthermore, this invention encompasses a method for stimulating the sphenopalatine ganglion and increasing cerebral blood flow, comprising the step of administering, orally via transmucosal route, a composition containing non-pungent derivatives of capsaicin, as defined above, as the sole active ingredient, simultaneously with or following the diagnosis of vascular neurological diseases associated with decreased cerebral blood flow.

[0021] In this way, the present invention provides an innovative and safe alternative for the treatment of these conditions, eliminating the barriers of intolerance and irritation present in formulations based on pungent capsaicin, while maintaining its therapeutic efficacy.

[0022] BRIEF DESCRIPTION OF THE FIGURES

[0023] Figure 1. This is a schematic view of the human oral cavity showing the placement site of the mucoadhesive oral tablet on the posterior surface of the palate, designed to allow transmucosal chemical stimulation of the sphenopalatine ganglion by administering non-pungent capsaicin derivatives, in order to increase cerebral blood flow. DETAILED DESCRIPTION OF THE INVENTION

[0024] According to this invention, non-pungent derivatives of capsaicin, in their tautomeric forms and pharmacologically acceptable salts, are used as the sole active ingredient to produce stimulation of the sphenopalatine ganglion and, as a result, increase cerebral blood flow by transmucosal oral administration, in order to treat vascular neurological diseases associated with decreased cerebral blood flow.

[0025] The term “Treatment”, as used herein, means that the compound is administered concurrently with or following the diagnosis of a neurovascular disease related to decreased cerebral blood flow, for the purpose of producing an effective increase in cerebral blood flow.

[0026] The term “Vascular Neurological Disease,” as used here, refers to diseases in which there is a restriction of cerebral blood flow as a result of a mechanism of: Narrowing (stenosis), Blockage (embolism), or Rupture (hemorrhage). These include, but are not limited to: cerebrovascular disease, stroke, transient ischemic attack, intracerebral hemorrhage, subarachnoid hemorrhage, delayed cerebral ischemia, vasospasm of intracranial vessels, intracranial atherosclerosis, carotid atherosclerosis, vertebrobasilar atherosclerosis, migraine, vascular cognitive impairment, and vascular dementia. The term “Cerebral Blood Flow,” as used here, means the blood supply to the brain at any given time, with a normal value of 40–50 mL / 100 g of brain tissue / min.

[0027] The term “Oral Mucosa”, as used here, refers to the endodermal lining of the oral cavity, which extends to the skin of the lips.

[0028] The non-pungent capsaicin derivatives described in this invention maintain the ability to stimulate the sphenopalatine ganglion without significantly activating peripheral TRPV1 receptors, thus avoiding the burning and irritation sensation. Examples of non-pungent derivatives include, but are not limited to:

[0029] 1. Olvanil (N-oleoylvanillamide): A derivative with analgesic activity and low pungency.

[0030] 2. Nonivamide (PAVA): Commonly used in topical formulations due to its stability and low irritant profile.

[0031] 3. Civamide: Cis isomer of capsaicin, with less activation of peripheral TRPV1.

[0032] 4. N-(4-hydroxyphenyl)-nonanamide: With hydroxylated substituents that reduce pungency.

[0033] 5. N-(4-methoxyphenyl)-octanamide: With methoxylated groups that decrease the interaction with peripheral TRPV1. These derivatives allow safe and tolerable transmucosal administration, ensuring adequate absorption and effective activation of the sphenopalatine ganglion to increase cerebral blood flow.

[0034] Dosage and Administration

[0035] According to this invention, the equivalent dose of a non-pungent capsaicin derivative can be determined based on its affinity for the TRPV1 receptor, its potency (EC50), and its transmucosal bioavailability, compared to standard capsaicin. These doses can be adjusted to achieve a pharmacological effect equivalent to that observed with capsaicin within predetermined ranges.

[0036] Administration can be initiated at the time of diagnosis of a neurovascular disease, within an interval of 1 to 180 minutes, preferably between 1 and 30 minutes, and / or for a duration of 20 to 240 minutes, for example, 20 minutes.

[0037] Pharmaceutical Composition

[0038] In addition to the non-pungent capsaicin derivative, the pharmaceutical composition includes a pharmaceutically acceptable vehicle, which may be in solid or liquid form:

[0039] Solid vehicles: Powders, granules, capsules, tablets, films.

[0040] Liquid vehicles: Water-based, oil-based, water-in-oil or oil-in-water emulsions, dispersions.

[0041] Preferably, the composition is in the form of a mucoadhesive tablet, which can have any geometric shape (rectangular, circular, oval, etc.).

[0042] The composition is preferred to provide a controlled release of the non-pungent capsaicin derivative over a period of 20 to 240 minutes, preferably 20 to 60 minutes.

[0043] The mucoadhesive tablet includes at least:

[0044] Non-pungent derivative of capsaicin as the sole active ingredient.

[0045] At least one diluent: Microcrystalline cellulose, lactose, mannitol, starch, sorbitol.

[0046] At least one bioadhesive agent: Chitosan, alginate, carboxymethylcellulose, hydroxypropylcellulose. At least one binder: Povidone, hydroxypropylmethylcellulose, polyvinyl alcohol.

[0047] At least one prolonged-release agent: Polysaccharides (hypromellose, xanthan gum, alginates). Additional additives: Lubricants (magnesium stearate), fluidizers (colloidal silicon dioxide), flavorings (xylitol, aspartame). The concentration of excipients is adjusted to ensure:

[0048] Diluents: 10-60% by weight.

[0049] Bioadhesives: 0.5-5% by weight.

[0050] Prolonged-release agents: 10-60% by weight.

[0051] Additional additives: 0.1-10% by weight.

[0052] Administration Method

[0053] The method comprises the transmucosal oral administration of a non-pungent capsaicin derivative to a subject in need, either simultaneously with or following the diagnosis of a vascular neurological disease resulting from decreased cerebral blood flow.

[0054] In some cases, the subject may also be given:

[0055] 1. Intravenous thrombolysis with tissue plasminogen activator (tPA).

[0056] 2. Mechanical thrombectomy, preferably in combination with tPA.

[0057] Application of the Mucoadhesive Tablet

[0058] The tablet adheres to the posterior surface of the palate as illustrated in Figure 1, applying slight pressure to ensure it stays in place. It is recommended to apply it after proper oral hygiene to optimize absorption.

[0059] In this way, the present invention provides an effective and safe alternative for the treatment of vascular neurological diseases, avoiding the adverse effects associated with pungent capsaicin derivatives and allowing for greater therapeutic adherence.

[0060] EXAMPLES:

[0061] This invention will be better understood in light of the following examples, which are included for illustrative purposes only and are not intended to limit the scope of the invention, which is defined by the appended claims.

[0062] Calculation of the Equivalent Dose of Non-Pungent Capsaicin Derivatives

[0063] According to the prior patent, the recommended dose of capsaicin for transmucosal chemical stimulation of the sphenopalatine ganglion and increased cerebral blood flow is 66 to 99 pmol of capsaicin. In the present invention, this validated dose is maintained, but the amount of each non-pungent capsaicin derivative is adjusted according to its specific molecular weight to ensure adequate pharmacological equivalence.

[0064] The amount of non-pungent derivative (D) is calculated using the following formula (II):

[0065] D = (99[imol') x (Molecular weight of the derivative')

[0066] Where:

[0067] • D: It is the amount of non-pungent derivative equivalent to 99 pmol of capsaicin.

[0068] • 99 pmol: Corresponds to the optimal dose recommended in the previous patent.

[0069] • Molecular weight of the derivative: Varies depending on the compound used.

[0070] Therefore, each example will adjust its dose based on this formula, ensuring an appropriate pharmacological equivalence with respect to capsaicin.

[0071] Example 1: Tablet with Olvanil (N-oleoylvanillamide, molecular weight 379.5 g / mol) Applying formula (II), D = 37.55mg.

[0072] Tablet Preparation

[0073] A mixture was prepared with the following components:

[0074] Non-pungent derivative: Olvanil (37.55 mg)

[0075] Diluent: Microcrystalline cellulose (20% by weight)

[0076] Bioadhesive agent: Chitosan (5% by weight)

[0077] Binder: Povidone (3% by weight)

[0078] Lubricant: Magnesium stearate (1% by weight)

[0079] Fluidifier: Colloidal silicon dioxide (1% by weight)

[0080] Wetting agent: Distilled water

[0081] The mixture was compressed into an oval, mucoadhesive tablet designed for immediate release. The process included the steps of preparing a homogeneous mixture of the active ingredients and excipients, stabilizing the active components, controlled drying to ensure the stability of the active ingredient, and final compression into a shape suitable for transmucosal oral administration.

[0082] Example 2: Tablet with Nonivamide (N-vanillyl-n-nonamide, molecular weight 293.4 g / mol) Applying formula (II), D = 29.01 mg.

[0083] Tablet Preparation

[0084] A mixture was prepared with the following components:

[0085] Non-pungent derivative: Nonivamide (29.01 mg)

[0086] Diluent: Lactose (25% by weight) Bioadhesive agent: Sodium alginate (4% by weight)

[0087] Binder: Hydroxypropyl methylcellulose (2.5% by weight)

[0088] Lubricant: Magnesium stearate (1% by weight)

[0089] Fluidizer: Talc (1% by weight)

[0090] Wetting agent: Distilled water

[0091] The mixture was compressed into a circular, mucoadhesive tablet, optimized for immediate release. The process comprised the steps of homogeneous mixing of active ingredients and excipients, chemical stabilization of the components, uniform drying of the formulation, and final compression into a shape suitable for transmucosal oral administration.

[0092] Example 3: Tablet with Civamide (Cis isomer of Capsaicin, molecular weight 305.4 g / mol)

[0093] Applying formula (II), D = 30.19mg.

[0094] Tablet Preparation

[0095] A mixture was prepared with the following components:

[0096] Non-pungent derivative: Civamide (30.19 mg)

[0097] Thinner: Mannitol (25% by weight)

[0098] Bioadhesive agent: Carboxymethylcellulose (3% by weight)

[0099] Binder: Povidone (2% by weight)

[0100] Lubricant: Stearic acid (1% by weight)

[0101] Fluidifier: Colloidal silicon dioxide (1% by weight)

[0102] Wetting agent: Distilled water

[0103] The mixture was compressed into a rectangular mucoadhesive tablet, optimized for immediate release. The process included the steps of homogeneous mixing of the active ingredients and excipients, stabilization of the active ingredients, controlled drying to ensure chemical stability, and final compression into a shape suitable for transmucosal oral administration.

[0104] Example 4: Extended-Release Tablet with N-Vanillylnonanamide (N-Vanillylnonanamide, molecular weight 311.4 g / mol)

[0105] Applying formula (II), D = 30.82mg.

[0106] Tablet Preparation

[0107] A formulation was prepared with the following components:

[0108] Non-pungent derivative: N-Vanillylnonanamide (30.82 mg)

[0109] Diluent: Sorbitol (20% by weight)

[0110] Bioadhesive agent: Hydroxyethylcellulose (4% by weight) Binder: Polyvinylpyrrolidone (2% by weight)

[0111] Extended-release agent: Sodium alginate (30% by weight)

[0112] Lubricant: Magnesium stearate (1% by weight)

[0113] Fluidifier: Colloidal silicon dioxide (1% by weight)

[0114] Wetting agent: Distilled water

[0115] The mixture was compressed under high pressure to form an oval mucoadhesive tablet, designed for prolonged release over a period of 20 to 240 minutes. The process comprised the steps of preparing a homogeneous mixture of the active ingredients and excipients, chemically stabilizing the active components, controlled drying to ensure the stability of the active ingredient, and final compression into a shape suitable for transmucosal oral administration.

[0116] LITERATURE

[0117] Ahad, MA, KR Kumaran, T. Ning, NI Mansor, MA Effendy, T. Damodaran, K. Lingam, HA Wahab, N. Nordin and P. Liao (2020). "Insights into the neuropathology of cerebral ischemia and its mechanisms." Reviews in the Neurosciences 31 (5): 521 -538.

[0118] Chauhan, S., S. Gaidhane, G. P. Priya, P. Sharma, M. Bhat, S. Sharma, M. R. Kumar, A. Sinha, Q. S. Zahiruddin, N. Dev, G. Bushi, D. Jena, M. Shabil, S. Sah, R. Syed, K. Kundra, A. Dash and S. K. Samal (2024). "Burden of neurologic diseases in BRICS countries (1990 to 2021): an analysis of 2021 Global Burden of Disease Study." Front Neurol 15: 1500551.

[0119] Ghozy, S., S. E. O. Kacimi, A. Y. Azzam, R. A. Farahat, A. Abdelaal, K. M. Kallmes, G. Adusumilli, J. J. Heit, R. Kadirvel and D. F. Kallmes (2022). "Successful mechanical thrombectomy in acute ischemic stroke: revascularization grade and functional independence." J Neurointerv Surg 14(8): 779-782.

[0120] Goyal, N., G. Tsivgoulis, A. Pandhi, K. Malhotra, R. Krishnan, M. F. Ishfaq, B. Krishnaiah, C. Nickele, V. Inoa-Acosta, A. H. Katsanos, D. Hoit, L. Elijovich, A. Alexandrov and A. S. Arthur (2019). "Impact of pretreatment with intravenous thrombolysis on reperfusion status in acute strokes treated with mechanical thrombectomy." J Neurointerv Surg 11(11): 1073-1079.

[0121] Marquez-Romero, J. M. and K. I. Sanchez-Ramirez (2024). "Sphenopalatine ganglion stimulation for the treatment of cerebrovascular ischemia." Clin Auton Res.

[0122] Powers, W. J., C. P. Derdeyn, J. Biller, C. S. Coffey, B. L. Hoh, E. C. Jauch, K. C. Johnston, S. C. Johnston, A. A. Khalessi, C. S. Kidwell, J. F. Meschia, B. Ovbiagele, D. R. Yavagal and C. American Heart Association Stroke (2015). "2015 American Heart Association / American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute IschemicStroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association / American Stroke Association." Stroke 46(10): 3020-3035.

[0123] Yadollahikhales, G., A. Borhani-Haghighi, M. Torabi-Nami, R. Edgell and S. Cruz-Flores (2016). "Flow Augmentation in Acute Ischemic Stroke." Clin Appl Thromb Hemost 22(1): 42-51.

[0124] POSIBILIDAD DE APLICACIÓN INDUSTRIAL

[0125] According to the present invention, it is possible to provide a transmucosal oral therapeutic drug that uses non-pungent capsaicin derivatives to chemically stimulate the sphenopalatine ganglion and thereby increase cerebral blood flow in an effective and tolerable manner.

[0126] This invention represents an innovative solution to prevent or reduce brain damage associated with decreased cerebral blood flow in vascular neurological conditions, such as stroke, vasospasm secondary to subarachnoid hemorrhage, and vascular dementia, among others.

[0127] Thanks to the elimination of the irritating effects associated with pungent capsaicin, the formulations described in this invention allow for greater adherence to treatment, offering a practical and safe alternative for clinical use.

[0128] It is hereby stated that, as of this date, the best method known to the applicant for carrying out the aforementioned invention is that which is clear from the present detailed description, including the specific formulations and methods of administration described in the examples. This invention has high potential for industrial application, as it allows for the large-scale production of mucoadhesive tablets with non-pungent capsaicin derivatives, using standard pharmaceutical technologies and guaranteeing the stability, bioavailability, and therapeutic efficacy of the final product.

[0129] Furthermore, the versatility of the proposed formulations facilitates their adaptation to different patient profiles and clinical scenarios, which reinforces their viability for being marketed as an advanced therapeutic option in vascular neurology.

Claims

CLAIMS 1. A pharmaceutical composition comprising a pharmaceutically acceptable vehicle and a non-pungent capsaicin derivative, the compound having the following general formula (I): R - C6H4- NHCO - (CH2') n - R' in its tautomeric forms and pharmacologically acceptable salts, as the sole active ingredient, for use in stimulating the sphenopalatine ganglion and increasing cerebral blood flow, where the composition is administered orally via transmucosal injection.

2. A composition for use according to claim 1, wherein the composition is administerable to a subject simultaneously with or following the diagnosis of a neurovascular disease resulting from decreased cerebral blood flow.

3. A composition for use according to claim 1 or 2, wherein the vascular neurological disease resulting from decreased cerebral blood flow is selected from: cerebrovascular disease, cerebral infarction, transient ischemic attack, intracerebral hemorrhage, subarachnoid hemorrhage, late cerebral ischemia, vasospasm of intracranial vessels, intracranial atherosclerosis, carotid atherosclerosis, vertebrobasilar atherosclerosis, migraine, cognitive impairment of vascular origin, and vascular dementia.

4. A composition for use according to any one of claims 1 to 3, wherein the compound of general formula (I) corresponds to a derivative selected from: Olvanil (N-oleoylvanillamide), Nonivamide (N-vanillyl-n-nonamide), Civamide (cis isomer of capsaicin), N-(4-hydroxyphenyl)-nonanamide, N-(4-methoxyphenyl)-octanamide and N-vanillylnonanamide, including, but not limited to, other non-pungent derivatives of capsaicin that retain the ability to stimulate the sphenopalatine ganglion without significantly activating peripheral TRPV1 receptors.

5. A composition for use according to any of claims 1 to 4, wherein the preparation comprises a non-pungent derivative of capsaicin or a pharmacologically acceptable salt thereof.

6. A composition for use according to any of claims 1 to 5, wherein said composition is formulated for prolonged release of the non-pungent derivative of capsaicin for a period of at least 20 minutes and up to 240 minutes.

7. A composition for use according to any of claims 1 to 6, wherein said composition is formulated in the form of a mucoadhesive oral tablet.

8. A composition for use in accordance with any of claims 1 and 4-7, wherein said composition provides an intake of a non-pungent capsaicin derivative (expressed as equivalent base) of between 33 and 265 pg, preferably from 66 to 99 pg, adjusted according to the relative potency (EC50) and specific molecular weight of the derivative.

9. A composition for use according to any of claims 6 and 7, wherein said composition is formulated to release a non-pungent capsaicin derivative for a period of between 20 and 240 minutes and is administered orally transmucosally within the first 1 to 180 minutes after the diagnosis of a vascular neurological disease.

10. A composition for use in accordance with any of claims 1 and 4-7, wherein the following are also administerable: intravenous thrombolysis with tissue plasminogen activator (tPA) or mechanical thrombectomy, preferably simultaneously with intravenous thrombolysis with tissue plasminogen activator.

11. The use of a composition comprising a non-pungent derivative of capsaicin, as the sole active ingredient, for the manufacture of a medicament intended to stimulate the sphenopalatine ganglion and increase cerebral blood flow.

12. A method for stimulating the sphenopalatine ganglion and increasing cerebral blood flow, comprising the step of administering orally transmucosally to a subject in need a non-pungent derivative of capsaicin, simultaneously with or after the diagnosis of a vascular neurological disease resulting from decreased cerebral blood flow.

13. A composition for use in accordance with any of the preceding claims, wherein the mucoadhesive tablet provides controlled release of the non-pungent capsaicin derivative over a period of 20 to 240 minutes, ensuring optimal absorption and effective stimulation of the sphenopalatine ganglion.

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