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BR-102024017659-A2 - Use of SS-caryophyllene inclusion complex with methyl-SS-cyclodextrin for the treatment of epilepsy.

BR102024017659A2BR 102024017659 A2BR102024017659 A2BR 102024017659A2BR-102024017659-A2

Abstract

Despite the pharmacological potential of β-caryophyllene (β-CNF), there are several limitations such as low water solubility, volatility, sensitivity to humidity, and easy oxidation when exposed to light and oxygen. These physicochemical characteristics result in low bioavailability of β-CNF and consequently may limit its application in pharmaceuticals, nutraceuticals, and functional foods. The present invention relates to the use of the inclusion complex of β-caryophyllene with methyl-β-cyclodextrin (β-CNF/MβCD), obtained by the co-evaporation/lyophilization method with a molar ratio of the components β-caryophyllene (β-CNF) and methyl-β-cyclodextrin (MβCD) in a 1:1 molar ratio, with application in the areas of biotechnology, food industry, pharmaceuticals, and cosmetics. More specifically, the present invention relates to the neuropharmacological activity of β-CNF/MβCD compared to β-CNF on generalized tonic-clonic seizures induced by the chemoconvulsants pilocarpine, pentylenetetrazol, and isoniazid in female Swiss mice. The main result obtained from the present invention was the demonstration that β-CNF/MβCD was effective in neuropharmacological activity at a lower dose than free β-CNF, representing an important pharmaceutical and technological alternative with potential application.

Inventors

  • GEORGE LAYLSON DA SILVA OLIVEIRA
  • BRUNA VOUGADO DA SILVA
  • LUCIANO DA SILVA LOPES
  • ANA PAULA DOS SANTOS CORREIA LIMA DA SILVA

Assignees

  • INSTITUTO FEDERAL DE EDUCAÇÃO, CIÊNCIA E TECNOLOGIA DE MATO GROSSO
  • UNIVERSIDADE FEDERAL DO PIAUÍ (UFPI)

Dates

Publication Date
20260310
Application Date
20240828

Claims (7)

  1. 1. USE OF THE β-CARYOPHYLENE INCLUSION COMPLEX WITH METHYL-β-CYCLODEXTRIN FOR THE TREATMENT OF EPILEPSY, characterized by exhibiting antiepileptic activity that was confirmed in delaying generalized tonic-clonic seizures in Swissfemale mice.
  2. 2. USE OF THE β-CARYOPHYLENE INCLUSION COMPLEX WITH METHYL-β-CYCLODEXTRIN FOR THE TREATMENT OF EPILEPSY, according to claim 1, characterized by its methodologies in delaying generalized tonic-clonic seizures induced by the chemoconvulsants pilocarpine, pentylenetetrazol and isoniazid.
  3. 3. USE OF THE β-CARYOPHYLENE INCLUSION COMPLEX WITH METHYL-β-CYCLODEXTRIN FOR THE TREATMENT OF EPILEPSY, according to claims 1 and 2, characterized by being an agent with antiepileptic activity at various doses, including 200 mg/kg.
  4. 4. USE OF THE β-CARYOPHYLENE INCLUSION COMPLEX WITH METHYL-β-CYCLODEXTRIN FOR THE TREATMENT OF EPILEPSY, according to claims 1, 2 and 3, characterized by being a biotechnological product with antiepileptic activity in solid, semi-solid and/or liquid forms, and can be obtained by viable drying of any solvent or extractive solution, regardless of the proportions between the solvents and by technique and/or preparation process.
  5. 5. USE OF THE β-CARYOPHYLENE INCLUSION COMPLEX WITH METHYL-β-CYCLODEXTRIN FOR THE TREATMENT OF EPILEPSY, according to claims 1, 2, 3 and 4, characterized by being a biotechnological product with antiepileptic activity for its pharmaceutical use by any route of administration, in animals and/or humans.
  6. 6. USE OF THE β-CARYOPHYLENE/METHYL-β-CYCLODEXTRIN INCLUSION COMPLEX AS AN ANTIOXIDANT AGENT, according to claims 1, 2, 3, 4 and 5, characterized by the preparation of a medicament/agent with antiepileptic activity, has potential for use in the food, pharmaceutical and cosmetic industries.
  7. 7. USE OF THE β-CARYOPHYLENE/METHYL-β-CYCLODEXTRIN INCLUSION COMPLEX AS AN ANTIOXIDANT AGENT, according to claims 1, 2, 3, 4, 5 and 6, characterized by being more soluble than free β-caryophyllene without complexation.

Description

Field of invention [001] The present invention relates to the use of the β-caryophyllene inclusion complex with methyl-β-cyclodextrin for application in the biotechnology and food, pharmaceutical and cosmetic industries. More specifically, the present invention relates to the antiepileptic activity of the β-caryophyllene inclusion complex with methyl-β-cyclodextrin and its use in the formulation of pharmaceutical products. The antiepileptic activity of the β-caryophyllene inclusion complex with methyl-β-cyclodextrin was confirmed in delaying generalized tonic-clonic seizures induced by the chemoconvulsants pilocarpine, pentylenetetrazol and isoniazid in female Swiss mice. Fundamentals of the invention [002] The occurrence of generalized or partial epileptic seizures in the brain is characteristic of a neurological disease called epilepsy, which has a very serious impact on health due to its neurobiological, cognitive, psychological, and social consequences (Szilágyi et al., 2014; Nabbout; Kuchenbuch, 2020; Mesraoua et al., 2023). Annually, 2.4 million new cases of epilepsy are diagnosed, and according to the World Health Organization (WHO), epilepsy is one of the most common neurological diseases, affecting approximately 50 million people in the world's population, which has already exceeded 8 billion (WHO, 2019). The treatment of epileptic seizures is considered quite complicated due to the wide spectrum of epileptic disorders and manifestations, and also because people with this disease frequently suffer from comorbidities that need to be addressed (Pfisterer et al., 2020). Of those treated with the latest generation of antiepileptic drugs, 70% are partially treated with relapsed epileptic seizures, 30% have uncontrolled epileptic seizures, and 80% of those affected by this disease live in developing countries (Engel JR, 2014; WHO, 2019). [003] From this perspective, phytochemicals such as terpenes (monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes) can be highlighted, as they have multiple therapeutic applications and are important constituents of essential oils that can be found in nature as hydrocarbons or other forms containing oxygen atoms such as alcohols, ketones, aldehydes, acids, or lactones (Wiart, 2014; Pina et al., 2021; Oliveira et al., 2023). Among the classes of terpenes, sesquiterpenes, which are composed of three isoprene units, have attracted considerable interest from a chemical, structural, chemotaxonomic point of view, and mainly because many exhibit various pharmacological activities directed at disorders of the central nervous system (Nuutinen, 2018; Oliveira et al., 2023). [004] Regarding sesquiterpenes, bicyclic caryophyllene stands out, which includes the alpha (α), beta (β), and gamma (γ) isomers. Among these isomers, β-caryophyllene [(1R,4E,9S)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene] has double bonds and plays an important role in sesquiterpenoid chemistry. Based on chemical composition analyses such as gas chromatography coupled with mass spectrometry (GC-MS), β-caryophyllene is among the major sesquiterpenes in essential oils of Croton campestris A. St.-Hil (Oliveira-Tintino et al., 2018), Severinia monophylla Linn (Satyal et al., 2019), and Baccharis amygdalina Griseb. (Ascari et al., 2019), Artemisia annua Linn. (Qinghao) (Cavar et al., 2012), Cannabis sativa Linn (Ibrahim et al., 2019), Psidium cattleyanum Sabine (Bruna Guimarães et al., 2023) and several species of the genus Copaifera (Arruda et al., 2019). [005] Despite the pharmacological potential of β-caryophyllene, there are several limitations such as low water solubility, volatility, sensitivity to humidity, and easy oxidation when exposed to light and oxygen. These physicochemical characteristics result in low bioavailability of β-caryophyllene and consequently may limit its application in the areas of biotechnology, food and pharmaceutical industries (Santos et al., 2017; Amalraj et al., 2020; Alizadeh et al., 2022). [006] Complexing natural compounds such as sesquiterpenes with natural or derived cyclodextrins has been a relevant strategy to improve aqueous solubility, stability, dissolution rate, and bioavailability (Lima et al., 2016; Heimfarth et al., 2022). With the ability to transport pharmacological compounds that can be highly potent and specific, carbohydrates have received considerable interest as encapsulation materials due to their natural origin, biodegradability, and biocompatibility, as well as their hydrophilic character and ease of chemical modification combined with low cost and the possibility of large-scale manufacturing (Buchwald; Bodor, 2016; Cid-Samamed et al., 2022). The application of these oligosaccharides in pharmaceutical formulations is mainly for oral, parenteral, nasal, or pulmonary administration. Non-clinical studies have shown that cyclodextrins can be used pharmacologically for central nervous system disorders, considering their specific