WO2014168467A1

WO2014168467A1 - Product and use of a compound having analgesic, anti-inflammatory and antipyretic properties

Info

Publication number: WO2014168467A1
Application number: PCT/MX2014/000055
Authority: WO
Inventors: Carlos Ramirez Serrano
Original assignee: Carlos Ramirez Serrano
Priority date: 2013-04-11
Filing date: 2014-04-09
Publication date: 2014-10-16
Also published as: MX2013004050A

Abstract

The invention relates to a novel product having a synergistic activity, suitable for different pharmacological uses, such as to treat pain and inhibit inflammation and fever, comprising a salicylate, such as acetylsalicylic acid or analogues, and a raw extract of Asteraceae, such as Matricaria spp. The compound can be in any physical state. The properties of the product have a potentiated effect in smaller doses compared with the components individually, the side effects of which are reduced or virtually harmless. Acetylsalicylic acid has anti-clotting properties, whereas this product does not exhibit this characteristic. The invention is produced from substances that have been used since ancient times, and provides a novel combination offering an alternative with hitherto unknown properties.

Description

PRODUCT AND USE OF A COMPOSITE WITH ANALGESIC, ANTIINF L AMATORY AND ANTIPIRETIC PROPERTIES

FIELD OF THE INVENTION

The invention is in the pharmacological field that refers to a new compound with synergistic capacity for the treatment of pain, anti-inflammatory and antipyretic, which is constituted by a salicylate and a crude extract of Matricaria spp. BACKGROUND OF THE INVENTION

According to the literature, chamomile {Matricaria spp.) Produces apigenin secondary metabolism, alpha-bisabolol which are considered to have antiseptic, anti-inflammatory properties and inhibit pepsin secretion without affecting acid secretion, sesquiterpenes, terpenoids are also found , flavonoids, coumarins (herniarin, umbelliferone-fungistatic), phenylpropanoids (chlorogenic acid, caffeic acid), flavones (apigenin-preventive chemo, luteolin), flavonoids (quercetin, rutin) and polyacetylenes. There is medical evidence that these species have anxiolytic (anti-anxiety) properties, and also to treat stress and insomnia, for example, they can fix gamma-aminobutyric acid receptors, modulate monoamine neurotransmissions, and also neuroendocrine effects. It is noteworthy that coumarins have antihemorrhagic properties, and it has been proven that with other medications has drug-drug interaction. Chamomile extracts are used as anti-inflammatories, which includes topical hemorrhoid treatment; they also have antihyperglycemic, and anticancer effects in in vitro and animal studies. For this study it is worth highlighting an American innovation where extracts of Matricaria sp. (McCloskey, 2010)

With regard to salicylates such as pure acetylsalicylic acid, it has been manufactured and marketed since 1899. In the beginning and in the natural way they are drugs extracted from willow and other plants with similar properties, whose references are present in the papyri of civilizations Egyptians for 4 thousand years, and were employed for the treatment of fever since the Ancient and Middle Ages. Willow bark extract was known for this effect, in addition to pain and inflammation treatment in the 18th century. It was until 1853 when Chemist Charles Frederick Gerhardt combined acetic chloride together with sodium salicylate and produced acetylsalicylic acid for the first time; later during the same century its chemical structure was established and more efficient ways of producing it were developed. In 1897, Bayer scientists began research on acetylsalicylic acid because it was the least irritating of the rest of salicylates. Two years later in 1899, Aspirin (Aspirin in Spanish) appeared to be sold worldwide and became a "generic name." Where it should be noted that the rights of the brand were lost or sold in many countries and its popularity grew during the Spanish Influenza in 1918 for its effectiveness, and is currently considered medically as absolutely counterproductive, since it is recommended not to use it during a viral infection . The popularity of aspirin declined with the incursion of Paracetamol (acetaminophen / paracetamol) in 1956 and Ibuprofen in 1962. Thanks to John Vane's research, the basic mechanism of its effect was discovered, while medical studies demonstrated the efficiency of Aspirin as an anticoagulant. Therefore, so far this century is used as a preventive treatment against heart attacks due to the activity of the acid. These medications are obtained from the willow (Salix spp.) And other plants that metabolize salicylates, are references of the ancestral pharmacopoeia to be used as analgesics, antipyretic, anti-inflammatory. Willow bark was used for medicinal purposes in the west since Hippocrates in the 5th century BC. of C. who recommended it for delivery and fever; The encyclopedist Celsius mentions in his treatise on Medicine the extracts of willow leaf for signs of inflammations: irritation, fever, swelling and pain. He is also mentioned in Dioscorides's De Materia Medica, and in Pliny the Eider's Natural History. Also since the time of Galen, the use of botanical pharmacopoeia is also referred to in the Arab and Roman empires. The start of salicylates as medicines was in 1763, when a letter from Edward Stone was presented at a meeting of the Royal Society where the power of willow bark extracts to cure malaria was described, ie fever, pain and fatigue. The process to obtain the extract was previously carried out by Stone in 1758, through the collection of willow bark, its dehydration and spraying, with which he treated malaria patients for 5 years, which showed consistency in the results, and are similar to those demonstrated by the Peruvian bark, however, only controls malaria does not cure it because the Salicin is less potent than quinine from the Peruvian crust, however it was a cheap source of control.

In the nineteenth century, Organic Chemistry began its development in Europe, whereby the culture of isolation and purification of active ingredients began, including those containing willow bark. Joseph Buchner managed to obtain almost pure salicin crystals in 1828, which Henri Leroux improved a year later. It was until 1838 that the Italian chemist Raffaele Piria developed a method to obtain the salicylic acid he had previously discovered in 1830, Johann Pagenstecher in Spiraea ulmaria; However, this researcher was the one who established that the product of Piria and the extract of Spiraea was salicylic acid. All of the above caused that the following decades the use of salicylate drugs (salicin, salicylic acid and sodium salicylate) increased its application in the treatment of pain, fever and inflammations, despite the collateral gastritis caused. By 1880 the German industry began the development of coal tar dyes, which boosted a line of new medicines. The Antifebrine ™ trademark of derivatives of dye compounds, whose antipyretic properties were discovered by accident in 1886, which was the inspiration for the then small company Bayer (Friedrich Bayer & Company), to start the development of new anti-fever medications such as Phenacetin , and sedatives such as Sulfonal and Trional.

Regarding the synthesis of acetylsalicylic acid, Bayer initiated a project to develop new drugs in 1897 with a group of pharmacologists led by Arthur Eichengrün, and its analysis by another group that led Heinrich Dreser, who along with Felix Hoffman developed the acid acetylsalicylic, whose brand Aspirin ™ is known and used throughout the world. The latter began the search for a less irritating salicylic acid substitute. Previously other chemists tried to accelerate the mentioned acid, and thus produce acetylsalicylic acid. Earlier in 1853, Charles FredericGerhardt, obtained from the mixture of acetic chloride and sodium salicylate, acetic salicylic anhydride (wasserfreieSalicylsaure-Essigsáure), but when trying to dissolve it with sodium carbonate, they decompose into sodium salts of salicylic acid and acetic acid. Also in 1859 von Gilm produced it, only that he called it acetylated salicylic acid by the reaction of salicylic acid and acetic chloride. In 1869 three chemists (Schróder, Prinzhorn and raut) tested both processes, of which they concluded that the product is acetylsalicylic acid whose structure is awarded to Prinzhorn, by the acetyl group linked to a phenolic oxygen. This product was sold without a brand, but it contains impurities. Hoffmann in 1897 developed the best process by reacting salicylic acid and acetic anhydride. This required analysis and tests that were highly positive. Subsequently, medical studies were carried out, however they were arrested because negative cardiac effects were detected by the treatment against rheumatism. It should be noted that the only one who received royalties for sales was Dreser for the publication he made where he never mentions either Hoffman or Eichengrün.

The use of acetylsalicylic acid with any trademark, during the Spanish influenza pandemic in 1918 demonstrated effectiveness in reducing fever and thus fighting viral infection, however, the legend is currently printed that is not recommended for side effects (see Warnings and Recommendations in the container box). When the patent expired in the USA in 1917, Sterling already possessed the Aspirin brand, however it became a generic name of acetylsalicylic acid, it is also worth noting the bad reputation he had during that pandemic, due to the rumor that he would ingest the infectious agent, which favored the appearance of new brands for said acid in the United States of America. The mechanisms of action as analgesic, anti-inflammatory and antipyretic of acetylsalicylic acid were unknown until the mid-twentieth century, which were the most successful times of this drug; one of its creators considered (Heinrich Dreser) that it acted on the central nervous system to relieve pain, which was accepted since its launch in the market; However, in 1958 Harry Collier biochemist of the Cia. Parke Davis, found during his investigation to find the relationship of the effect between quinines and acetylsalicylic acid in Guinea pigs, by first giving them the acid, the bronchial constriction generated by bradykinin is inhibited ; and even by cutting the vagus nerve, the effect of bradykinin and acetylsalicylic acid is not inhibited, which is why I conclude that it acts directly to reduce inflammation and reduce or remove pain. Later in the University of London. After Priscila Piper, together with John Vane, performed tissue bioassays and tested the biochemical effects of cascading and anaphylactic shocks on rabbit aorta and pig lung tissues, they found that the acid inhibits the production of a substance. which produces the contraction, which was later identified as prostaglandin, a finding published in Nature in 1971 where they concluded that products similar to acetylsalicylic acid inhibit contracture; It was then discovered that it inhibits the production of cyclooxygenase, which converts arachidonic acid into prostaglandin. It is worth noting the recent innovations of this medicine as Hassan et al. (2009), which presents a new machine to produce acetylsalicylic acid, also Sakova et al. (2012) propose a new analgesic mixture with a salicylate and stearic acid.

The objective of this development was to find the effects of the compound resulting from a salicylate together with the extract of an asteracea for pain control, which remedies inflammation and fever. This new compound has great advantages since it shows synergistic effect in the treatment of pain, how anti-inflammatory and antipyretic because fever is not generated. It was found that it depends on the ratio and concentration of salicylate and extract of Matricaria spp.

BRIEF DESCRIPTION OF THE INVENTION

Natural and synthetic salicylates, as well as infusions of Manza Lla (Matricaria spp.), Have recognized properties, which is why they are traditionally used for the treatment of pain, inflammation and fever; However, for a dental pain, they are of little use, because they diminish the sensation during a period of time that can only be minutes. When there are cavities that cause pain the problem increases, so its use is practically nil. However, it is known that both salicylate or its analogues and the extract obtained from Matricaria spp. by solvents of different polarity, which can be alcohol and / or water, demonstrate interaction with other drugs or medications when they are transcribed in a treatment. However, the components of the present invention are of low risk since during the evaluation they do not show collateral effects, and sise observed that the relationship and concentration are the key to their synergistic effect, so it was decided to evaluate them in different relationship and concentration in order of determining the effect on pain treatment. The effect was discovered by the interaction of the components, where their activity demonstrated a duration 12, 24 or more hours; which means synergy. This effect can vary from decrease to complete suppression for months, through a treatment that implies a consumption that does not exceed what people traditionally use of analgesics and infusions per day. Where there was also no change in stomach acid or bleeding problems in case of injuries, due to the collateral effect of salicylates.

DRAWINGS

Figure represents the way to prepare the liquid form (L), to dissolve the salicylate (S) and the crude extract (E) of Matricaria spp.

Figuralb represents the compound in solution (CL) competent to be used as an analgesic, anti-inflammatory and antipyretic.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention there is a new compound that can be used as an analgesic, anti-inflammatory and antipyretic, given by the formation of a compound obtained by salicylates plus the extracts obtained from chamomile {Matricaria spp.) With higher polarity solvents such as ethanol and / or water, which have recognized properties, which are traditionally used for the treatment of pain, inflammation and fever; However, for a dental pain, they are of little use, because they only diminish the sensation during a period of time that can be several minutes. When there are cavities that cause pain the problem increases, so its use is practically nil. However, it is known that both salicylate or its analogues, as well as the extract obtained from Matricaria spp., Have demonstrated interaction with other drugs or medications as described in different references. However, the components of the present invention are considered low risk if they are consumed as long as they do not interact with other medications with which they show side effects. In this invention it was observed that the relationship and concentration are the key to its synergistic effect, so it was decided to evaluate them in different relationship and concentration in order to determine the effect in the treatment of pain (Table 1). Table 1. Relations and Concentrations of Salicylate and Extract of Matricaria spp.

Ratio Concentration / mg Effect

50/50 250-500 / 250-500 Analgesic, anti-inflammatory and anti-fever

25/75 125-250 / 375-750 Analgesic, anti-inflammatory and anti-fever

75/25 500-750 / 125- 250 Short duration (minutes)

90/10 405-900 / 45-100 Short duration (minutes)

The effect was discovered by the interaction of the components, where its analgesic activity showed a duration that can vary between 12 and 24 hours, you can even be longer than this period; which implies that the two components when joining have synergy, in this way it was found that the complex compounds have activity and effects that must be tested in order to improve the characteristics of the drugs. This effect can vary and depends on the ratio and concentration of both components, which ranges from the decrease to the complete suppression of pain, which was evaluated for 4 months, through a treatment that involves a consumption that does not exceed what people traditionally use analgesics and infusions per day. Where it should be noted that no significant changes in stomach acid were observed, nor was excessive bleeding observed in case of wounds, which is a recognized side effect of salicylates for their anticoagulant effect.

This new invention demonstrates that herbalism or pharmacopoeia can be the sustenance of innovations, because medicinal plants are known, whose traditional use has roots and validity in different countries with ancestral reminiscences, additionally the need of the human being to connect with nature, implies the use of products with safety features that allow sustainability. This compound is an example that the combination of different substances is the key to developing new pharmacological or medicinal compounds, because pure active ingredients generally have undesirable side effects. REFERENCES

Hassan, A., Bagherzadeh, E., Anthony, R.G., Borsinger, G. and Hassan, A. 2009. High shear process for aspirin production. PCT International Publication: WO2009003024A2. WIPO / WIPO, Geneva Switzerland. Pp .; 1 -21.

McCloskey, D.A. 2010. Analgesic oil containing plant based extracts from solar infusions. Publication of patent application US20101 19633A1. USPTO U.S.A.A.A. Pp .: 1-6.

Sokova, O., Vladovicova, B., Kabzanova, A., Kormonova, V. and Zoricak, S. 2010.

Combined oral formulation with controlled relée of acetylsalicylic acid and a method for the preparation. International PCT Publication: WO2012159593 A2. WIPO / WIPO Geneva, Switzerland. Pp .: 1-12.

Claims

1. A product with synergistic activity composed of a salicylate plus a crude extract of an asteracea; characterized in that the compound can be in a physical state that can be liquid or solid, where the salicylate that can be acetylsalicylic acid or another analogue must be in a gr or ml, in a ratio that can vary from 1 to 99 or from 99 to 1, and its concentration may vary from 10 to 990 mg; plus the crude extract of the Asterácea is from the plant classified as Matricaria spp. (chamomile) and must be present in a ratio that can vary from 1 to 99 or from 99 to 1 and its concentration can vary between 10 and 990 mg, this extract can be obtained with solvents of different polarity, which can be alcohol and / or water or other similar solvent; This product shows competence as an analgesic, anti-inflammatory and antipyretic.

2. A use of the compound generated by a salicylate which can be acetylsalicylic acid or an analogous product and the crude extract of an Asteraceae which can be Matricaria spp. or an analogous extract, such as analgesic, anti-inflammatory and antipyretic.