WO2000038699A1 - COMPOSITIONS OBTAINED FROM $i(MANGIFERA INDICA L.) - Google Patents

COMPOSITIONS OBTAINED FROM $i(MANGIFERA INDICA L.) Download PDF

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Publication number
WO2000038699A1
WO2000038699A1 PCT/CU1999/000007 CU9900007W WO0038699A1 WO 2000038699 A1 WO2000038699 A1 WO 2000038699A1 CU 9900007 W CU9900007 W CU 9900007W WO 0038699 A1 WO0038699 A1 WO 0038699A1
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WO
WIPO (PCT)
Prior art keywords
mixture
terpenoids
steroids
polyphenols
fatty acids
Prior art date
Application number
PCT/CU1999/000007
Other languages
Spanish (es)
French (fr)
Inventor
Alberto Julio NUÑEZ SELLES
Eleuterio Paez Betancourt
Daniel Amaro Gonzalez
Jhoany Acosta Esquijarosa
Juan Aguero Aguero
Raúl CAPOTE HERNANDEZ
María Rosa GARCIGA HERNANDEZ
Iván Gastón MORALES LACARRERE
Oscar Garcia Pulpeiro
Gabino Garrido Garrido
Gregorio Martinez Sanchez
Miguel Morales
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Centro De Quimica Farmaceutica
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Publication date
Application filed by Centro De Quimica Farmaceutica filed Critical Centro De Quimica Farmaceutica
Priority to CA002358013A priority Critical patent/CA2358013A1/en
Priority to AU22531/00A priority patent/AU2253100A/en
Publication of WO2000038699A1 publication Critical patent/WO2000038699A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers

Definitions

  • the present invention relates primarily to the pharmaceutical, food and cosmetic industries and in particular to obtaining a mixture of active ingredients derived from the Mangifera indica L. species, among which are polyphenols, terpenoids, steroids, fatty acids and microelements, which confer useful properties to the compositions that contain them for their high value as a dietary supplement for the improvement of the quality of life in patients with degenerative diseases, in the anti-aging treatment, as well as for their consumption by healthy people .
  • Prior art Although there is a documented ethnopharmacological knowledge of the use of different parts of the Mangifera indica L. tree (roots, stems, bark, flowers and fruits) for use in the treatment of pathologies such as menorrhagia (Chopra, RN 1933.
  • patent application No. WO 96/16632 Al refers to obtaining cosmetic or pharmaceutical compositions that use “mangiferin or its derivatives in pure form or extract as an active ingredient. of plants "and the formulation of emulsions, aqueous or hydroalcoholic gels, creams, oils, aqueous or hydroalcoholic lotions, lipstick, shampoo or conditioner, etc., for the photoprotection of the skin, lips and hair.
  • This compound that is obtained primarily by extraction from the leaves of the Aphloia and Mangiferina species, it was found to possess anti-ultraviolet, anti-collagenase and anti-elastase, free anti-radical and anti-tyrosinase activity.
  • An objective of the present invention is to obtain a mixture of active ingredients such as polyphenols, terpenoids, steroids, fatty acids and microelements from the bark of the stem of the Mangifera indica L. tree.
  • Another object of the invention is to obtain formulations from the mixture of the aforementioned active ingredients with important pharmacological, cosmetic and dietary properties for oral, topical and parenteral use.
  • the formulations object of the invention have a particular qualitative and quantitative composition of active ingredients obtained from Mangifera indica L. with distinctive properties, based on the following:
  • the object formulations of the present invention are completely of natural origin, where components of Pharmacological activity (polyphenols, terpenoids and steroids) with others of dietary value (fatty acids and microelements).
  • the mixture of components of pharmacological activity and of dietary value give the formulations a high antioxidant capacity that leads to the elevation of the indices with which the quality of life and anti-aging treatment is evaluated, as well as supplement dietary, which substantially differentiates it from other similar products in the market.
  • Table I Qualitative and quantitative composition of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements used in the formulations of the present invention.
  • L. which once collected and preserved under appropriate conditions, is they go through a drying process until they reach a humidity between 4 and 12%. It is then passed through a decoction process with a polar solvent such as water, or one containing a hydroxyl group with a carbon chain between 0 and 6 linear or cyclic carbon atoms selected from the group consisting of methanol, ethanol, dioxane or cycloexanol or mixture from them.
  • a polar solvent such as water, or one containing a hydroxyl group with a carbon chain between 0 and 6 linear or cyclic carbon atoms selected from the group consisting of methanol, ethanol, dioxane or cycloexanol or mixture from them.
  • the virgin plant matter is exhausted at a temperature ranging from 65 ° C to 101 ° C, and subsequently the drying of the extract is carried out by atomization, until a dark brown solid that melts with decomposition between 216 and 218 ° C and whose physicochemical properties are described in Table II
  • Table II Physicochemical properties of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements that are used in the formulations of the present invention.
  • the mixture used as an active ingredient of the formulations has antioxidant, anti-inflammatory, analgesic and antispasmodic activity, whose action leads to a significant increase in parametric indices of quality of life in patients immunocompromised by degenerative diseases, more specifically in patients with different types of neoplasms. It was found in these patients that the general condition reached an average index of 3.5 on a parametric scale of 5 in periods ranging from 1 to 6 months of treatment with the formulations object of the present invention.
  • the daily dose of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements suitable to achieve the pharmacological activities object of the invention is between 10 and 100 mg / Kg of body weight, using oral routes as the most appropriate routes of administration. of tablets, coated tablets or dragees or flavored suspension, and the topical, in the form of cream, ointment or lotion, although it can also be administered rectally, vaginally or parenterally.
  • the unit dose of the formulations, for oral administration preferably contains as active ingredient between 8.0 and 55.0% by weight of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements. This dose is achieved by mixing the active ingredient with different excipients in the pharmaceutical formulation, either as binders, disintegrants, lubricants, flavorings or dyes.
  • the unit dose of the formulations, for topical administration preferably contains as active ingredient between 1.0 and 4.0% by weight of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements. This dose is achieved by mixing the active ingredient with different excipients, either as vehicles or stabilizers.
  • the formulations included in the present invention are harmless, according to the results obtained in the acute, subchronic and chronic toxicity tests carried out in rodents; do not reveal irritating activity; they do not present genotoxic potential and they do not present clastogenic activity. No side effects have been detected in patients treated with the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements object of the present invention.
  • Example 1 The starting point was 100 kilograms of vegetable raw material obtained from the bark of the stem of the Mangifera indica L. tree, to which a process of solid-liquid extraction by means of a mixture of water / ethanol with 70% water. The extract thus obtained is concentrated at a temperature of 85 ° C and subsequently spray dried with air at an inlet temperature of 150 ° C and 80 ° C at the outlet until a dark brown powder is obtained. In this way, 7.5 Kg of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements described above are obtained.
  • the physicochemical properties of the mixture were the following: water content between 5 and 9%; solubility, 1.2 g / 10 mL 0.1 mol / L NaOH; pH between 5 and 7; relative density 1.0 g / cm 3 .
  • the purity of this mixture was 93%.
  • Example 2 From the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained in Example 2, 300 mg coated tablets of said mixture were made per tablet, which contained the components presented in Table IV.
  • Example 2 From the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained in Example 2, the 10% by weight flavored suspension of said mixture was made, which contained the components presented in Table V.
  • Example 6 From the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained in Example 2, the lipophilic ointment was prepared at 2.4% by weight of said mixture, which contained the components presented in the Table VILE
  • VIL Table Pharmaceutical formulation of lipophilic ointment
  • Example 4 A group of 38 affected patients with different types of neoplasms coated tablets containing 300 mg of the aforementioned mixture as active ingredient (Example 3), or 3 mL of flavored suspension containing 10% by weight of said mixture were supplied ( Example 4).
  • the cream was applied at 2.4% by weight (Example 5) or the ointment at 2.4% by weight (Example 7) of said mixture on the affected surface, depending on the type of lesion.
  • the unit dose (300 mg) was given orally 4 times a day and the cream or ointment was applied as many times as necessary.
  • the treatment was maintained for 6 months and the quality of life was evaluated through internationally accepted survey systems for measuring the general condition of the patient. All patients were interviewed before starting treatment and 6 months after starting treatment.
  • the first number corresponds to the classification in Table VIII and the second number is the consecutive order.
  • Example 7 In the same group of patients as in Example 7, within the study described above and with a similar methodology, the index of depression before starting treatment and at 6 months of treatment. The depression rate was evaluated as Major, Minor or Normal according to the scale that appears in Table XI.
  • Coated tablets containing 300 mg of the mixture were supplied to a group of 122 affected patients with different types of neoplasms. cited above as active ingredient (Example 3), or -3 mL of flavored suspension containing 10% by weight of said mixture (Example 4).
  • active ingredient Example 3
  • -3 mL of flavored suspension containing 10% by weight of said mixture Example 4
  • the cream was applied at 2.4% by weight (Example 5) or the ointment at 2.4% by weight (Example 7) of said mixture on the affected surface, depending on the type of lesion.
  • the classification of the patients, according to the diagnosis, was the one reflected in Table XIII.
  • the unit dose (300 mg) was given orally 4 times a day and the cream or ointment was applied as many times as necessary.
  • the treatment was maintained between 1 and 12 months, according to the initial state of the patient, and the general condition of the patient was evaluated at the end of the treatment through internationally accepted survey systems for measuring the general condition of the patient, hematological, biochemical and clinical analyzes. . All patients were evaluated before starting and at the end of treatment. The evaluation of the general condition of the patient at the end of the treatment was carried out on the basis of the parametric scale that appears in Table XIV. Table XTV Patient evaluation criteria at the end of the study
  • the capacity of the active ingredient used in the formulations in the stimulation of nitric oxide production was evaluated, as an important messenger involved in immunological events such as T lymphocyte differentiation, macrophage activation and anti-tumor defense mechanisms.
  • the effect of the active ingredient was studied through the possible stimulation of nitric oxide-synthase induced (iNOS) and its comparison with the challenge by LPS and the effect induced by dexamethasone.
  • the animals used male Wistar rats between 150 and 175 g in weight) were removed the food 16 hours before the treatments.
  • Dexamethasone was administered 1 hour before administration of LPS and 30 minutes after administration of the active ingredient at doses between 10 and 200 mg / kg body weight.
  • the animals were sacrificed at 18 hours of treatment, blood was drawn to obtain the sera and the concentration of nitrates and nitrites was determined.
  • Table XVI The results of the study are shown in Table XVI.
  • the analgesic action of the active ingredient used in the formulations was evaluated by tests of analgesia by formalin and acetic acid, respectively, in mice. Balb C mice of 6 weeks of age and body weight between 20 and 23 grams were used. Indomethacin and a negative control group were used as reference substance. The analgesic effect, measured by the reduction of the number of licks, was obtained from a dose of the active ingredient of 5 mg / kg body weight.
  • Example 12 The anti-inflammatory activity of the active ingredient used in the formulations was evaluated by testing the induction of plantar edema by carrageenans in Pirbright guinea pigs of 4 weeks of age and body weight between 200 and 300 grams.
  • the antispasmodic activity of the active ingredient used in the formulations was evaluated by studying its effect on contracted rat ileum, in 6-week-old Sprague Dawley rats weighing 300 to 350 grams. The rats were sacrificed and the ileum was removed for dissection. Each ileum was separated into four rings and mounted on 10 mL isolated organ vessels with modified Tyrode solution and allowed to stabilize for 1 hour, making changes to the solution every 15 minutes. Tyrode solution modified with 100 mM potassium chloride was added and contraction was induced. Subsequently, the active ingredient solution was added in increasing concentrations from 25 to 1 304 ⁇ g / mL. The relaxation was expressed as the percentage of decrease in the maximum tension obtained in the presence of the active ingredient and the results are shown in Table XVIII.
  • the in iteriter anti-oxidant activity of the active ingredient used in the formulations described above was evaluated by assessing its capacity for spontaneous self-oxidation, inhibition of phospholipid peroxidation in rat brain homogenate and the bleomycin-iron system, respectively. , uptake of hydroxyl radicals and hypochlorous acid.
  • the active ingredient was shown to have protective activity against peroxidation of phospholipids enzymatically in rat brain homogenate. This protection proved to be dose-dependent and the average protective dose was 0.018% (w / v) as seen in Table XIX.
  • the hydroxyl radical sequestration capacity found was remarkably high and it was found that the concentration (w / v) in which the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements exhibits a 50% reduction of hydroxyl radicals generated was 0.011 %. This demonstrates the high antioxidant capacity of the object of the invention against one of the radical oxygen species that is most frequently associated with processes of deterioration of the human organism.
  • the sequestration capacity of hypochlorous acid that was found was also notable, since the concentration (w / v) at which the 50% reduction in the concentration of this species was detected was 0.04%. This demonstrates the high antioxidant capacity of the object of the invention by protecting the antiproteinase alpha one, which is degraded by hypochlorous acid.
  • Example 14 The antioxidant properties described in Example 14 for the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements object of the invention have not been previously described for any other product. natural at such low concentration levels, demonstrating its effectiveness in the chemoprevention of biological events related to aging and degenerative pathologies that cause considerable stress in the human organism, which was demonstrated in patients with neoplasms according to Examples 7, 8 and 9.
  • anti-oxidant properties are linked to physiological processes related to inflammation and pain, described in Examples 10, 11, 12 and 13 which allow correlating the anti-inflammatory, analgesic and antispasmodic observed with the high capacity of inhibition of lipid peroxidation, spontaneous autoxidation, sequestration of hydroxyl radicals and hypochlorous acid, which gives the object of the invention distinctive characteristics, due to its high efficiency, not previously reported for another product on the market.

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Abstract

The present invention relates essentially to the pharmaceutical, food and cosmetic industries and in particular to the preparation of formulations of active principles which are derived from the plant Mangifera indica L. amongst which are the polyphenols, the terpenoids, the steroids, the fatty acids and microelements which have anti-oxidating, anti-inflammatory, analgesic and antispasmodic properties thereby conferring to said formulations a high value as dietary supplements for the improvement of the quality of life of patients suffering from degenerative diseases, anti-aging treatment as well as for the consumption by healthy persons.

Description

COMPOSICIONES OBTENIDAS A PARTIR DE Mangifera indica COMPOSITIONS OBTAINED FROM Mangifera indica
L.L.
Sector Técnico La presente invención se relaciona fundamentalmente con las industrias farmacéutica, alimenticia y cosmética y en particular con la obtención de una mezcla de principios activos derivados de la especie Mangifera indica L. entre los que se encuentran polifenoles, terpenoides, esteroides, ácidos grasos y microelementos, los cuales les confieren propiedades útiles a las composiciones que los contienen por su alto valor como suplemento dietético para la mejoría de la calidad de vida en pacientes con enfermedades degenerativas, en el tratamiento anti-envejecimiento, así como para su consumo por personas sanas. Técnica anterior Aunque existe un conocimiento etnofarmacológico documentado de la utilización de diferentes partes del árbol Mangifera indica L. (raíces, tallos, corteza, flores y frutos) para su empleo en el tratamiento de patologías tales como la menorragia (Chopra, R. N. 1933. Indigenous Drugs of India. Their Medical and Economic Aspects. The Art Press, Calcultta, India), la escabiosis (Singh, Y. N. 1986. Tradicional Medicine in Fiji: Some herbal folk cures used by Fiji Indians.: J Ethnopharmacol 15 1: 57-88), las diarreas (Darías S. V. y cois, 1989. New contribution to the ethnopharmacological study of the Canary Islands. J Ethnopharmacol 25 1: 77 92; Le Grand, A. 1989. Anti-infectious phytotherapy of the tree-Savannah, Senegal, Western África III: A Review of the phytochemical substances and anti-microbial activity of 43 species. J Ethnopharmacol 25 3: 315-338; Ponce-Macotela, M. y cois. 1994. In vitro antigiardiasic activity of plant extracts. R. Rev Invest Clin 46 5: 343-347; Muanza, D. N y cois. 1994. Antibacterial and antifungal activities of nine medicine plants from Zaire. Int J Pharmacolog 32 4: 337-345), la sífilis (Singh, Y. N. 1986. Tradicional Medicine in Fiji: Some herbal folk cures used by Fiji Indians.: J Ethnopharmacol 15 1: 57-88), la diabetes (Anjaneyulu y cois. 1989. Triterpenoids from Mangifera indica. Phytochemistry 28 5: 1471-1477; Muanza, D. N y cois. 1994. Antibacterial and antifungal activities of nine medicine plants from Zaire. Int J Pharmacolog 32 4: 337-345), las infecciones cutáneas (Le Grand, A. 1989. Anti-infectious phytotherapy of the tree- Savannah, Senegal, Western África III: A Review of the phytochemical substances and anti-microbial activity of 43 species. J Ethnopharmacol 25 3: 315-338), los dolores de dientes (Le Grand, A. 1989. Anti-infectious phytotherapy of the tree-Savannah, Senegal, Western África III: A Review of the phytochemical substances and anti-microbial activity of 43 species. J Ethnopharmacol 25 3: 315-338; Chhabra, S. C. y col, 1987 Plants used in tradictional medicine in Eastern Tanzania. I. Pteridophytes and Angiosperms. J Ethnopharmacol 21 3: 253-277) y la anemia (Muanza, D. N y cois. 1994. Antibacterial and antifungal activities of nine medicine plants from Zaire. Int J Pharmacolog 32 4: 337-345), no se conocen formulaciones para uso alguno donde se utilicen como ingrediente activo la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos como la obtenida a partir de la corteza del tallo de este árbol.Technical Sector The present invention relates primarily to the pharmaceutical, food and cosmetic industries and in particular to obtaining a mixture of active ingredients derived from the Mangifera indica L. species, among which are polyphenols, terpenoids, steroids, fatty acids and microelements, which confer useful properties to the compositions that contain them for their high value as a dietary supplement for the improvement of the quality of life in patients with degenerative diseases, in the anti-aging treatment, as well as for their consumption by healthy people . Prior art Although there is a documented ethnopharmacological knowledge of the use of different parts of the Mangifera indica L. tree (roots, stems, bark, flowers and fruits) for use in the treatment of pathologies such as menorrhagia (Chopra, RN 1933. Indigenous Drugs of India, Their Medical and Economic Aspects, The Art Press, Calcultta, India), Scabiosis (Singh, YN 1986. Traditional Medicine in Fiji: Some herbal folk cures used by Fiji Indians .: J Ethnopharmacol 15 1: 57-88 ), diarrhea (Darías SV et al., 1989. New contribution to the ethnopharmacological study of the Canary Islands. J Ethnopharmacol 25 1: 77 92; Le Grand, A. 1989. Anti-infectious phytotherapy of the tree-Savannah, Senegal, Western Africa III: A Review of the phytochemical substances and anti-microbial activity of 43 species. J Ethnopharmacol 25 3: 315-338; Ponce-Macotela, M. and cois. 1994. In vitro antigiardiasic activity of plant extracts. R. Rev Invest Clin 46 5: 343-347; Mu anza, D. N and cois. 1994. Antibacterial and antifungal activities of nine medicine plants from Zaire. Int J Pharmacolog 32 4: 337-345), syphilis (Singh, YN 1986. Traditional Medicine in Fiji: Some herbal folk cures used by Fiji Indians .: J Ethnopharmacol 15 1: 57-88), diabetes (Anjaneyulu and cois 1989 Triterpenoids from Mangifera indica. Phytochemistry 28 5: 1471-1477; Muanza, D. N and cois. 1994. Antibacterial and antifungal activities of nine medicine plants from Zaire. Int J Pharmacolog 32 4: 337-345), skin infections (Le Grand, A. 1989. Anti-infectious phytotherapy of the tree- Savannah, Senegal, Western Africa III: A Review of the phytochemical substances and anti-microbial activity of 43 species. J Ethnopharmacol 25 3: 315-338), tooth pains (Le Grand, A. 1989. Anti-infectious phytotherapy of the tree-Savannah, Senegal, Western Africa III: A Review of the phytochemical substances and anti- microbial activity of 43 species. J Ethnopharmacol 25 3: 315-338; Chhabra, SC et al., 1987 Plants used in traditional medicine in Eastern Tanzania. I. Pteridophytes and Angiosperms. J Ethnopharmacol 21 3: 253-277) and anemia ( Muanza, D. N et al. 1994. Antibacterial and antifungal activities of nine medicine plants from Zaire. Int J Pharmacolog 32 4: 337-345), there are no known formulations for any use where the polyphenol mixture is used as an active ingredient, terpenoids, steroids, fatty acids and microelements as obtained gives from the bark of the stem of this tree.
Los reportes conocidos sobre la utilización etnofarmacológica de extractos de las partes del árbol Mangifera indica L. indican diferentes tipos de actividades biológicas, tales como insecticida, antigiardásico, antimalárico, antipirético y espasmolítico (Ponce-Macotela, M. y cois. 1994. In vitro antigiardiasic activity of plant extracts. R. Rev Invest Clin 46 5: 343-347; Awe, S. O. y cois. 1998. Antiplasmodial and antipyretic screening of Mangifera indica. Phytotherapy Res. 12:437-438; Kambu, K. y cois, 1990. Antispasmodic activity of extracts proceeding of plant antidiarrheic traditional preparations used in Kinshasa, Zaire. Ann Pharm Fr 48 4: 200-208), pero no existen reportes sobre estudios controlados que permitan correlacionar estos hallazgos con resultados clínicos en humanos.Known reports on the ethnopharmacological use of extracts from parts of the Mangifera tree indicate L. indicate different types of biological activities, such as insecticide, antiglastic, antimalarial, antipyretic and spasmolytic (Ponce-Macotela, M. and cois. 1994. In vitro antigiardiasic activity of plant extracts R. Rev Invest Clin 46 5: 343-347; Awe, SO et al. 1998. Antiplasmodial and antipyretic screening of Mangifera indica. Phytotherapy Res. 12: 437-438; Kambu, K. and cois, 1990. Antispasmodic activity of extracts proceeding of plant antidiarrheic traditional preparations used in Kinshasa, Zaire. Ann Pharm Fr 48 4: 200-208), but there are no reports on controlled studies that allow these findings to be correlated with clinical results in humans.
Por otra parte, la solicitud de patente No. WO 96/16632 Al se refiere a la obtención de composiciones cosméticas o farmacéuticas que empleen como ingrediente activo la "mangiferina o sus derivados en forma pura o en extracto de plantas" y la formulación de emulsiones, geles acuosos o hidroalcohólicos, cremas, aceites, lociones acuosas o hidroalcohólicas, lápiz labial, shampoo o acondicionador, etc., para la fotoprotección de la piel, los labios y el cabello. Este compuesto que se obtiene fundamentalmente mediante extracción a partir de las hojas de las especies Aphloia y Mangiferina, se le encontró que posee actividad anti-ultravioleta, anti-colagenasa y anti-elastasa, antiradicales libres y anti-tirosinasa. Divulgación de la InvenciónOn the other hand, patent application No. WO 96/16632 Al refers to obtaining cosmetic or pharmaceutical compositions that use "mangiferin or its derivatives in pure form or extract as an active ingredient. of plants "and the formulation of emulsions, aqueous or hydroalcoholic gels, creams, oils, aqueous or hydroalcoholic lotions, lipstick, shampoo or conditioner, etc., for the photoprotection of the skin, lips and hair. This compound that is obtained primarily by extraction from the leaves of the Aphloia and Mangiferina species, it was found to possess anti-ultraviolet, anti-collagenase and anti-elastase, free anti-radical and anti-tyrosinase activity.
Un objetivo de la presente invención es la obtención de una mezcla de ingredientes activos tales como polifenoles, terpenoides, esteroides, ácidos grasos y microelementos a partir de la corteza del tallo del árbol Mangifera indica L.An objective of the present invention is to obtain a mixture of active ingredients such as polyphenols, terpenoids, steroids, fatty acids and microelements from the bark of the stem of the Mangifera indica L. tree.
Otro objetivo de la invención es la obtención de formulaciones a partir de la mezcla de los principios activos anteriormente referidos con importantes propiedades farmacológicas, cosméticas y dietéticas para uso oral, tópico y parenteral.Another object of the invention is to obtain formulations from the mixture of the aforementioned active ingredients with important pharmacological, cosmetic and dietary properties for oral, topical and parenteral use.
Es también otro objetivo de la presente invención la utilización de estas formulaciones como suplemento dietético con propiedades antioxidante, antiinflamatoria, analgésica y antiespasmódica que conduzca a la elevación de los índices de la mejoría de la calidad de vida en pacientes con enfermedades degenerativas, su empleo como tratamiento anti-envejecimiento, así como para su consumo por personas sanas.It is also another objective of the present invention to use these formulations as a dietary supplement with antioxidant, anti-inflammatory, analgesic and antispasmodic properties that leads to the elevation of the indexes of the improvement of the quality of life in patients with degenerative diseases, their use as anti-aging treatment, as well as for consumption by healthy people.
Las formulaciones objeto de invención tienen una composición cualitativa y cuantitativa particular de ingredientes activos obtenidos a partir Mangifera indica L. con propiedades distintivas, sobre la base de lo siguiente:The formulations object of the invention have a particular qualitative and quantitative composition of active ingredients obtained from Mangifera indica L. with distinctive properties, based on the following:
A. No se conoce formulación alguna en las ramas farmacéutica, alimenticia y cosmética para la mejoría de la calidad de la vida, el tratamiento anti-envejecimiento o como suplemento dietético que se reivindica en la presente invención. B. Las formulaciones objetos de la presente invención son completamente de origen natural, donde se combinan componentes de actividad farmacológica (polifenoles, terpenoides y esteroides) con otros de valor dietético (ácidos grasos y microelementos).A. There is no known formulation in the pharmaceutical, food and cosmetic branches for the improvement of the quality of life, the anti-aging treatment or as a dietary supplement claimed in the present invention. B. The object formulations of the present invention are completely of natural origin, where components of Pharmacological activity (polyphenols, terpenoids and steroids) with others of dietary value (fatty acids and microelements).
C. La mezcla de componentes de actividad farmacológica y de valor dietético le confieren a las formulaciones una elevada capacidad antioxidante que conduce a la elevación de los índices con los que se evalúa la calidad de la vida y el tratamiento anti-envejecimiento, así como suplemento dietético, que lo diferencia sustancialmente de otros productos similares en el mercado.C. The mixture of components of pharmacological activity and of dietary value give the formulations a high antioxidant capacity that leads to the elevation of the indices with which the quality of life and anti-aging treatment is evaluated, as well as supplement dietary, which substantially differentiates it from other similar products in the market.
Para la determinación de la composición de la mezcla de la presente invención se llevaron a cabo los siguientes pasos:For the determination of the composition of the mixture of the present invention the following steps were carried out:
• Cromatografía de columna, cromatografía de placa de alta resolución y posterior identificación por técnicas espectroscópicas (polifenoles),• Column chromatography, high resolution plate chromatography and subsequent identification by spectroscopic techniques (polyphenols),
• Cromatografía líquida de alta resolución y cromatografía gaseosa capilar acoplada a espectrometría de masas (terpenoides y esteroides),• High resolution liquid chromatography and capillary gas chromatography coupled to mass spectrometry (terpenoids and steroids),
• Cromatografía gaseosa de alta resolución acoplada a espectrometría de masas (ácidos grasos),• High resolution gas chromatography coupled to mass spectrometry (fatty acids),
• Microscopía electrónica de barrido, análisis espectral de emisión atómica y espectrometría por fluorescencia de rayos X (microelementos). Los resultados de los análisis cualitativo y cuantitativo de la mezcla obtenida a partir de la corteza del árbol Mangifera indica L. se muestran en la Tabla I. • Scanning electron microscopy, spectral analysis of atomic emission and X-ray fluorescence spectrometry (microelements). The results of the qualitative and quantitative analyzes of the mixture obtained from the bark of the Mangifera indica L. tree are shown in Table I.
Tabla I. Composición cualitativa y cuantitativa de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos empleada en las formulaciones de la presente invención.Table I. Qualitative and quantitative composition of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements used in the formulations of the present invention.
Figure imgf000007_0001
Figure imgf000007_0001
Esta mezcla se obtiene de la corteza del tallo del árbol Mangifera indicaThis mixture is obtained from the bark of the stem of the Mangifera indica tree
L., la cual una vez recolectada y conservada en condiciones apropiadas, se pasan por un proceso de secado hasta alcanzar una humedad entre 4 y 12%. Luego se pasa por un proceso de decocción con un disolvente polar tal como agua, o uno que contenga un grupo hidroxilo con cadena carbonada entre 0 y 6 átomos de carbono lineal o cíclica seleccionado del grupo constituido por metanol, etanol, dioxano o cicloexanol o mezcla de ellos. Durante este proceso se agota la materia vegetal virgen a temperatura que oscila entre 65°C y 101°C, y posteriormente se lleva a cabo el secado del extracto por atomización, hasta obtener un sólido de color pardo oscuro que funde con descomposición entre 216 y 218°C y cuyas propiedades físico-químicas se describen en la Tabla IIL., which once collected and preserved under appropriate conditions, is they go through a drying process until they reach a humidity between 4 and 12%. It is then passed through a decoction process with a polar solvent such as water, or one containing a hydroxyl group with a carbon chain between 0 and 6 linear or cyclic carbon atoms selected from the group consisting of methanol, ethanol, dioxane or cycloexanol or mixture from them. During this process, the virgin plant matter is exhausted at a temperature ranging from 65 ° C to 101 ° C, and subsequently the drying of the extract is carried out by atomization, until a dark brown solid that melts with decomposition between 216 and 218 ° C and whose physicochemical properties are described in Table II
Tabla II. Propiedades físico-químicas de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos que se emplea en las formulaciones de la presente invención.Table II Physicochemical properties of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements that are used in the formulations of the present invention.
Figure imgf000008_0001
Figure imgf000008_0001
''Disolución de 1 gramo en 10 mL de agua destilada'' Dissolution of 1 gram in 10 mL of distilled water
Se ha encontrado que la mezcla empleada como ingrediente activo de las formulaciones posee actividad antioxidante, antiinflamatoria, analgésica y antiespasmódica, cuya acción conduce a un incremento significativo de los índices paramétricos de la calidad de vida en pacientes inmunodeprimidos por enfermedades degenerativas, más específicamente en pacientes con diferentes tipos de neoplasias. Se pudo comprobar en estos pacientes que el estado general alcanzó un índice promedio de 3,5 sobre una escala paramétrica de 5 en períodos que oscilaron entre 1 y 6 meses de tratamiento con las formulaciones objeto de la presente invención. La dosis diaria de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos adecuada para lograr las actividades farmacológicas objeto de invención es entre 10 y 100 mg/Kg de peso corporal, utilizando como vías de administración más adecuadas la oral, en forma de tabletas, tabletas revestidas o grageas o de suspensión saborizada, y la tópica, en forma de crema, ungüento o loción, aunque también puede ser administrado por vía rectal, vaginal o parenteral.It has been found that the mixture used as an active ingredient of the formulations has antioxidant, anti-inflammatory, analgesic and antispasmodic activity, whose action leads to a significant increase in parametric indices of quality of life in patients immunocompromised by degenerative diseases, more specifically in patients with different types of neoplasms. It was found in these patients that the general condition reached an average index of 3.5 on a parametric scale of 5 in periods ranging from 1 to 6 months of treatment with the formulations object of the present invention. The daily dose of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements suitable to achieve the pharmacological activities object of the invention is between 10 and 100 mg / Kg of body weight, using oral routes as the most appropriate routes of administration. of tablets, coated tablets or dragees or flavored suspension, and the topical, in the form of cream, ointment or lotion, although it can also be administered rectally, vaginally or parenterally.
La dosis unitaria de las formulaciones, para la administración por vía oral, contiene preferentemente como ingrediente activo entre el 8,0 y el 55,0 % en peso de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos. Esta dosis se logra al mezclar el ingrediente activo con diferentes excipientes en la formulación farmacéutica, ya sea como aglutinantes, desintegrantes, lubricantes, saborizantes o colorantes.The unit dose of the formulations, for oral administration, preferably contains as active ingredient between 8.0 and 55.0% by weight of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements. This dose is achieved by mixing the active ingredient with different excipients in the pharmaceutical formulation, either as binders, disintegrants, lubricants, flavorings or dyes.
La dosis unitaria de las formulaciones, para la administración por vía tópica, contiene preferentemente como ingrediente activo entre el 1,0 y el 4,0 % en peso de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos. Esta dosis se logra al mezclar el ingrediente activo con diferentes excipientes, ya sea como vehículos o estabilizantes.The unit dose of the formulations, for topical administration, preferably contains as active ingredient between 1.0 and 4.0% by weight of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements. This dose is achieved by mixing the active ingredient with different excipients, either as vehicles or stabilizers.
Las formulaciones que se incluyen en la presente invención son inocuas, de acuerdo a los resultados obtenidos en los ensayos de toxicidad aguda, subcrónica y crónica realizados en roedores; no revelan actividad irritante; no presentan potencial genotóxico y no presentan actividad clastogénica. No se han detectado efectos colaterales en los pacientes tratados con la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos objeto de la presente invención.The formulations included in the present invention are harmless, according to the results obtained in the acute, subchronic and chronic toxicity tests carried out in rodents; do not reveal irritating activity; they do not present genotoxic potential and they do not present clastogenic activity. No side effects have been detected in patients treated with the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements object of the present invention.
Los objetos de la invención se describen en detalle más adelante, donde se hace referencia a los ejemplos de realización, los cuales no limitan en ninguna circunstancia el alcance de la presente solicitud.The objects of the invention are described in detail below, where reference is made to the exemplary embodiments, which do not limit the scope of the present application under any circumstances.
Ejemplo 1 Se partió de 100 kilogramos de materia prima vegetal obtenida de la corteza del tallo del árbol Mangifera indica L. a la que se aplicó un proceso de extracción sólido-líquido mediante una mezcla de agua/etanol con agua al 70%. El extracto así obtenido se concentra a temperatura de 85°C y se seca con posterioridad por atomización con aire a una temperatura de entrada de 150°C y de 80°C a la salida hasta obtenerse un polvo de color pardo oscuro. De esta forma se obtienen 7,5 Kg de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos descrita con anterioridad.Example 1 The starting point was 100 kilograms of vegetable raw material obtained from the bark of the stem of the Mangifera indica L. tree, to which a process of solid-liquid extraction by means of a mixture of water / ethanol with 70% water. The extract thus obtained is concentrated at a temperature of 85 ° C and subsequently spray dried with air at an inlet temperature of 150 ° C and 80 ° C at the outlet until a dark brown powder is obtained. In this way, 7.5 Kg of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements described above are obtained.
Las propiedades físico-químicas de la mezcla fueron las siguientes: contenido de agua entre 5 y 9 %; solubilidad, 1,2 g/10 mL NaOH 0,1 mol/L; pH entre 5 y 7; densidad relativa 1,0 g/cm3. La pureza de esta mezcla fue de 93 %.The physicochemical properties of the mixture were the following: water content between 5 and 9%; solubility, 1.2 g / 10 mL 0.1 mol / L NaOH; pH between 5 and 7; relative density 1.0 g / cm 3 . The purity of this mixture was 93%.
Ejemplo 2Example 2
Se partió de 1 tonelada de materia prima vegetal obtenida de la corteza del tallo del árbol Mangifera indica L. al que se aplicó el mismo procedimiento del ejemplo anterior. Se obtuvieron 82 Kg de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos descrita con anterioridad. Las propiedades físico-químicas de la mezcla fueron las siguientes: contenido de agua, 3,8 %; solubilidad, 1,8 g/10 mL NaOH 0,1 mol L; pH, 5,9; densidad relativa, 1,1 g/cm3. La pureza de la mezcla fue de 97 %. La composición cualitativa y cuantitativa de las mezclas obtenidas en los Ejemplos 1 y 2 se muestra en la Tabla III.Starting from 1 ton of vegetable raw material obtained from the bark of the stem of the Mangifera indica L. tree to which the same procedure as in the previous example was applied. 82 Kg of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements described above were obtained. The physicochemical properties of the mixture were the following: water content, 3.8%; solubility, 1.8 g / 10 mL NaOH 0.1 mol L; pH, 5.9; relative density, 1.1 g / cm 3 . The purity of the mixture was 97%. The qualitative and quantitative composition of the mixtures obtained in Examples 1 and 2 is shown in Table III.
Tabla III. Composición cualitativa y cuantitativa de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenida en los Ejemplos 1 y 2Table III Qualitative and quantitative composition of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained in Examples 1 and 2
Figure imgf000010_0001
Ejemplo 3
Figure imgf000010_0001
Example 3
A partir de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenida en el Ejemplo 2 se confeccionaron tabletas revestidas de 300 mg de dicha mezcla por tableta, las cuales contenían los componentes que se presentan en la Tabla IV.From the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained in Example 2, 300 mg coated tablets of said mixture were made per tablet, which contained the components presented in Table IV.
Tabla IV. Formulación farmacéutica de tabletas revestidasTable IV Pharmaceutical formulation of coated tablets
Figure imgf000011_0001
Figure imgf000011_0001
Ejemplo 4Example 4
A partir de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenida en el Ejemplo 2 se confeccionó la suspensión saborizada al 10 % en peso de dicha mezcla, la cual contenía los componentes que se presentan en la Tabla V.From the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained in Example 2, the 10% by weight flavored suspension of said mixture was made, which contained the components presented in Table V.
Tabla V. Formulación farmacéutica de suspensión saborizadaTable V. Pharmaceutical formulation of flavored suspension
Figure imgf000011_0002
Ejemplo 5
Figure imgf000011_0002
Example 5
A partir de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenida en el Ejemplo 2 se confeccionó la crema hidrófila al 2,4 % en peso de dicha mezcla, la cual contenía los componentes que se presentan en la Tabla VI.From the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained in Example 2, the 2.4% by weight hydrophilic cream of said mixture was made, which contained the components presented in Table VI.
Tabla VI. Formulación farmacéutica de crema hidrófilaTable VI Pharmaceutical formulation of hydrophilic cream
Figure imgf000012_0001
Figure imgf000012_0001
Ejemplo 6 A partir de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenida en el Ejemplo 2 se confeccionó el ungüento lipófilo al 2,4 % en peso de dicha mezcla, la cual contenía los componentes que se presentan en la Tabla VILExample 6 From the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained in Example 2, the lipophilic ointment was prepared at 2.4% by weight of said mixture, which contained the components presented in the Table VILE
Tabla VIL Formulación farmacéutica de ungüento lipófiloVIL Table Pharmaceutical formulation of lipophilic ointment
Figure imgf000012_0002
Figure imgf000012_0002
Ejemplo 7Example 7
Se suministraron a un grupo de 38 pacientes afectados con diferentes tipos de neoplasias tabletas revestidas que contenían 300 mg de la mezcla citada con anterioridad como ingrediente activo (Ejemplo 3), o 3 mL de suspensión saborizada que contenía 10 % en peso de dicha mezcla (Ejemplo 4). En los casos de ulceraciones en piel se aplicó la crema al 2,4 % en peso (Ejemplo 5) o el ungüento al 2,4 % en peso (Ejemplo 7) de dicha mezcla sobre la superficie afectada, según el tipo de lesión. La clasificación de los pacientes, según el diagnóstico, fue la que se refleja en la Tabla VIII. Tabla VIII. Clasificación de pacientes incluidos en el estudioA group of 38 affected patients with different types of neoplasms coated tablets containing 300 mg of the aforementioned mixture as active ingredient (Example 3), or 3 mL of flavored suspension containing 10% by weight of said mixture were supplied ( Example 4). In cases of skin ulcerations, the cream was applied at 2.4% by weight (Example 5) or the ointment at 2.4% by weight (Example 7) of said mixture on the affected surface, depending on the type of lesion. The classification of the patients, according to the diagnosis, was the one reflected in Table VIII. Table VIII Classification of patients included in the study
Figure imgf000013_0001
Figure imgf000013_0001
Se suministró la dosis unitaria (300 mg) por vía oral 4 veces al día y se aplicó la crema o ungüento otras tantas veces en los casos que fue necesario. El tratamiento se mantuvo durante 6 meses y se evaluó la calidad de vida mediante sistemas de encuestas internacionalmente aceptadas para la medición del estado general del paciente Todos los pacientes fueron entrevistados antes de iniciar el tratamiento y 6 meses después de iniciado el tratamiento. La evaluación integral se cuantificó según la fórmula 5Xι + 5X2 + 3X3 + 2X4 + 4X5 + 2XΘ + 2X = P, donde Xi es la pregunta, la que se multiplica por un factor a criterio de los especialistas y P es el puntaje del paciente en la evaluación integral. Según el valor de P se clasificó el estado del paciente de acuerdo a las escalas que aparecen en la Tabla IX.The unit dose (300 mg) was given orally 4 times a day and the cream or ointment was applied as many times as necessary. The treatment was maintained for 6 months and the quality of life was evaluated through internationally accepted survey systems for measuring the general condition of the patient. All patients were interviewed before starting treatment and 6 months after starting treatment. The integral evaluation was quantified according to the formula 5Xι + 5X2 + 3X3 + 2X 4 + 4X5 + 2XΘ + 2X = P, where Xi is the question, which is multiplied by a factor at the discretion of the specialists and P is the patient's score in the integral evaluation. According to the value of P, the patient's condition was classified according to the scales shown in Table IX.
Tabla IX. Escala de evaluación de pacientesTable IX Patient Evaluation Scale
Figure imgf000013_0002
Los resultados se evaluaron mediante el test no paramétrico de Wilcoxon para una significación estadística p < 0,01. El resultado obtenido en la mejoría del estado general de los pacientes fue el que se refleja en la Tabla X.
Figure imgf000013_0002
The results were evaluated by the non-parametric Wilcoxon test for a statistical significance p <0.01. The result obtained in the improvement of the general condition of the patients was the one reflected in Table X.
Tabla X. Evaluación integral de los pacientes antes del tratamiento y 6 meses después del tratamiento.Table X. Comprehensive evaluation of patients before treatment and 6 months after treatment.
Figure imgf000014_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000015_0001
*E1 primer número se corresponde con la clasificación de la Tabla VIII y el segundo número es el orden consecutivo.* The first number corresponds to the classification in Table VIII and the second number is the consecutive order.
Al inicio del tratamiento, el 50,0 % de los pacientes clasificaron de REGULAR en su estado general y el 28,9 % de MAL. Después de 6 meses de tratamiento, sólo el 23,7 % de los pacientes clasificó de REGULAR y ninguno de MAL. El 60,5 % de los pacientes incluidos en el estudio (23) tuvo una mejoría sustancial en su estado general. El análisis estadístico de los resultados, evaluando no sólo el cambio de clasificación del paciente, sino también las variaciones de la puntuación, sobre la base de índices paramétricos, indicó que la mejoría del estado general del paciente con las formulaciones empleadas fue del 64,7 %.At the beginning of treatment, 50.0% of the patients classified REGULAR in their general condition and 28.9% of MAL. After 6 months of treatment, only 23.7% of the patients classified as REGULAR and none of MAL. 60.5% of the patients included in the study (23) had a substantial improvement in their general condition. The statistical analysis of the results, evaluating not only the change in the classification of the patient, but also the variations of the score, based on parametric indices, indicated that the improvement in the general condition of the patient with the formulations used was 64.7 %.
Ejemplo 8Example 8
En el mismo grupo de pacientes del Ejemplo 7, dentro del estudio descrito con anterioridad y con una metodología similar, se evaluó el índice de depresión antes de iniciar el tratamiento y a los 6 meses de tratamiento. El índice de depresión se evaluó de Mayor, Menor o Normal según la escala que aparece en la Tabla XI.In the same group of patients as in Example 7, within the study described above and with a similar methodology, the index of depression before starting treatment and at 6 months of treatment. The depression rate was evaluated as Major, Minor or Normal according to the scale that appears in Table XI.
Tabla XI. Escala de evaluación de pacientesTable XI Patient Evaluation Scale
Figure imgf000016_0001
Figure imgf000016_0001
Los resultados antes de iniciar el tratamiento y 6 meses después de tratamiento aparecen en la Tabla XII.The results before starting treatment and 6 months after treatment appear in Table XII.
Tabla XII. Evaluación del índice de depresión en pacientes tratados con las formulaciones de la presente invención.Table XII Evaluation of the depression index in patients treated with the formulations of the present invention.
Figure imgf000016_0002
Figure imgf000016_0002
El 44,7 % de los pacientes tratados con las formulaciones referidas tuvo una disminución notable del índice de depresión. El análisis estadístico de los resultados, evaluando no sólo el cambio de clasificación del paciente, sino también las variaciones de la puntuación, sobre la base de índices paramétricos, indicó que la mejoría del estado de depresión del paciente con las formulaciones empleadas fue del 59,1 %. Ejemplo 944.7% of the patients treated with the aforementioned formulations had a marked decrease in the depression rate. The statistical analysis of the results, evaluating not only the change in the classification of the patient, but also the variations of the score, based on parametric indices, indicated that the improvement in the patient's state of depression with the formulations used was 59, one %. Example 9
Se suministraron a un grupo de 122 pacientes afectados con diferentes tipos de neoplasias tabletas revestidas que contenían 300 mg de la mezcla citada con anterioridad como ingrediente activo (Ejemplo 3), o -3 mL de suspensión saborizada que contenía 10 % en peso de dicha mezcla (Ejemplo 4). En los casos de ulceraciones en piel se aplicó la crema al 2,4 % en peso (Ejemplo 5) o el ungüento al 2,4 % en peso (Ejemplo 7) de dicha mezcla sobre la superficie afectada, según el tipo de lesión. La clasificación de los pacientes, según el diagnóstico, fue la que se refleja en la Tabla XIII.Coated tablets containing 300 mg of the mixture were supplied to a group of 122 affected patients with different types of neoplasms. cited above as active ingredient (Example 3), or -3 mL of flavored suspension containing 10% by weight of said mixture (Example 4). In cases of skin ulcerations, the cream was applied at 2.4% by weight (Example 5) or the ointment at 2.4% by weight (Example 7) of said mixture on the affected surface, depending on the type of lesion. The classification of the patients, according to the diagnosis, was the one reflected in Table XIII.
Tabla XIII. Clasificación de pacientes incluidos en el estudioTable XIII Classification of patients included in the study
Figure imgf000017_0001
Figure imgf000017_0001
Se suministró la dosis unitaria (300 mg) por vía oral 4 veces al día y se aplicó la crema o ungüento otras tantas veces en los casos que fue necesario. El tratamiento se mantuvo entre 1 y 12 meses, según el estado inicial del paciente, y se evaluó el estado general del paciente al final del tratamiento mediante sistemas de encuestas internacionalmente aceptadas para la medición del estado general del paciente, análisis hematológicos, bioquímicos y clínicos. Todos los pacientes fueron evaluados antes de iniciar y al finalizar el tratamiento. La evaluación del estado general del paciente al finalizar el tratamiento se realizó sobre la base de la escala paramétrica que aparece en la Tabla XIV. Tabla XTV Criterios de evaluación de pacientes al finalizar el estudioThe unit dose (300 mg) was given orally 4 times a day and the cream or ointment was applied as many times as necessary. The treatment was maintained between 1 and 12 months, according to the initial state of the patient, and the general condition of the patient was evaluated at the end of the treatment through internationally accepted survey systems for measuring the general condition of the patient, hematological, biochemical and clinical analyzes. . All patients were evaluated before starting and at the end of treatment. The evaluation of the general condition of the patient at the end of the treatment was carried out on the basis of the parametric scale that appears in Table XIV. Table XTV Patient evaluation criteria at the end of the study
Figure imgf000018_0001
Figure imgf000018_0001
Los resultados de la "evaluación de estos pacientes después del tratamiento con las formulaciones son el que aparece en la Tabla XV.The results of the " evaluation of these patients after treatment with the formulations are as shown in Table XV.
Tabla XV Resultados en el estado general de pacientes con neoplasias después del tratamientoTable XV Results in the general state of patients with neoplasms after treatment
Figure imgf000018_0002
El 98 % de los pacientes después del tratamiento, con una duración entre 1 y 6 meses, tuvo una mejoría notable en los índices evaluados. Ejemplo 10
Figure imgf000018_0002
98% of patients after treatment, lasting between 1 and 6 months, had a marked improvement in the indexes evaluated. Example 10
Se evaluó la capacidad del ingrediente activo empleado en las formulaciones en la estimulación de la producción de óxido nítrico, como un importante mensajero involucrado en eventos inmunológicos tales como la diferenciación de linfocitos T, la activación de macrófagos y los mecanismos de defensa anti-tumoral. El efecto del ingrediente activo se estudió a través de la posible estimulación de la óxido nítrico-sintasa inducida (iNOS) y su comparación con el reto por LPS y el efecto inducido por la dexametasona. A los animales empleados (ratas Wistar machos entre 150 y 175 g de peso) se les retiró el alimento 16 horas antes de los tratamientos. La dexametasona se administró 1 hora antes de la administración de LPS y 30 minutos después de la administración del ingrediente activo a dosis entre 10 y 200 mg/Kg de peso corporal. Los animales se sacrificaron a las 18 horas de tratamiento, se extrajo la sangre para obtener los sueros y se determinó la concentración de nitratos y nitritos. Los resultados del estudio se muestran en la Tabla XVI.The capacity of the active ingredient used in the formulations in the stimulation of nitric oxide production was evaluated, as an important messenger involved in immunological events such as T lymphocyte differentiation, macrophage activation and anti-tumor defense mechanisms. The effect of the active ingredient was studied through the possible stimulation of nitric oxide-synthase induced (iNOS) and its comparison with the challenge by LPS and the effect induced by dexamethasone. The animals used (male Wistar rats between 150 and 175 g in weight) were removed the food 16 hours before the treatments. Dexamethasone was administered 1 hour before administration of LPS and 30 minutes after administration of the active ingredient at doses between 10 and 200 mg / kg body weight. The animals were sacrificed at 18 hours of treatment, blood was drawn to obtain the sera and the concentration of nitrates and nitrites was determined. The results of the study are shown in Table XVI.
TABLA XVI. Efecto del ingrediente activo empleado en las formulaciones sobre la producción de óxido nítrico en ratas.TABLE XVI Effect of the active ingredient used in the formulations on the production of nitric oxide in rats.
Figure imgf000019_0001
Figure imgf000019_0001
*Diferencia significativa para p < 0,01* Significant difference for p <0.01
El estudio demostró que el ingrediente activo que se emplea en las formulaciones de la invención estimula la producción de óxido nítrico a dosis por encima de 100 mg/Kg de peso corporal, lo que demuestra su efecto sobre los mediadores inmunológicos relacionados con la respuesta de esta enzima. Ejemplo 11The study showed that the active ingredient used in the formulations of the invention stimulates the production of nitric oxide at doses above 100 mg / kg body weight, which demonstrates its effect on the immunological mediators related to the response of this enzyme. Example 11
Se evaluó la acción analgésica del ingrediente activo empleado en las formulaciones mediante los ensayos de analgesia por formol y ácido acético, respectivamente, en ratones. Se emplearon ratones Balb C de 6 semanas de edad y peso corporal entre 20 y 23 gramos. Se empleó como sustancia de referencia la indometacina y un grupo control negativo. El efecto analgésico, medido por la reducción del número de lamidos, se obtuvo a partir de una dosis del ingrediente activo de 5 mg/Kg de peso corporal. Ejemplo 12 Se evaluó la actividad anti-inflamatoria del ingrediente activo empleado en las formulaciones mediante el ensayo de la inducción del edema plantar por carragenanos en cobayos Pirbright de 4 semanas de edad y peso corporal entre 200 y 300 gramos. A los animales se les retiró el alimento 24 horas antes del ensayo y se les indujo el edema por inyección subcutánea de lambda carragenano en la aponeurosis plantar. La inflamación se midió por desplazamiento del volumen de líquido. El ingrediente activo se suministró por vía oral 1 hora antes de la inyección de carragenano. Se utilizó como referencia el naproxeno sódico y se compararon los resultados con los de otros extractos de productos naturales. Los resultados se muestran en la Tabla xvπ.The analgesic action of the active ingredient used in the formulations was evaluated by tests of analgesia by formalin and acetic acid, respectively, in mice. Balb C mice of 6 weeks of age and body weight between 20 and 23 grams were used. Indomethacin and a negative control group were used as reference substance. The analgesic effect, measured by the reduction of the number of licks, was obtained from a dose of the active ingredient of 5 mg / kg body weight. Example 12 The anti-inflammatory activity of the active ingredient used in the formulations was evaluated by testing the induction of plantar edema by carrageenans in Pirbright guinea pigs of 4 weeks of age and body weight between 200 and 300 grams. The animals were removed 24 hours before the test and edema induced by subcutaneous injection of carrageenan lambda in the plantar aponeurosis. Inflammation was measured by displacement of the volume of fluid. The active ingredient was given orally 1 hour before the carrageenan injection. Sodium naproxen was used as a reference and the results were compared with those of other natural product extracts. The results are shown in Table xvπ.
TABLA XVII. Efecto anti-inflamatorio del ingrediente activo empleado en las formulaciones.TABLE XVII. Anti-inflammatory effect of the active ingredient used in the formulations.
Figure imgf000020_0001
Los resultados demostraron que la mezcla de ingredientes activos que se emplea en las formulaciones presenta actividad anti-inflamatoria a dosis de 1 000 mg/Kg de peso, de forma similar a la actividad del naproxeno sódico (4 mg/Kg) y la boldina (40 mg/Kg). Ejemplo 13
Figure imgf000020_0001
The results showed that the mixture of active ingredients used in the formulations has anti-inflammatory activity at a dose of 1,000 mg / kg of weight, similar to the activity of sodium naproxen (4 mg / kg) and boldine ( 40 mg / kg) Example 13
Se evaluó la actividad antiespasmódica del ingrediente activo que se emplea en las formulaciones mediante el estudio de su efecto sobre íleon de rata contraído, en ratas Sprague Dawley de 6 semanas de edad y entre 300 y 350 gramos de peso. Las ratas fueron sacrificadas y se les extrajo el íleon para disección. Cada íleon se separó en cuatro anillos y se montaron en vasos de órganos aislados de 10 mL con disolución Tyrode modificada y se dejó estabilizar por 1 hora, haciendo cambios de la disolución cada 15 minutos. Se adicionó disolución Tyrode modificada con cloruro de potasio 100 mM y se indujo la contracción. Con posterioridad se adicionó la disolución del ingrediente activo en concentraciones crecientes desde 25 hasta 1 304 μg/mL. La relajación fue expresada como el porciento de disminución de la tensión máxima obtenida en presencia del ingrediente activo y los resultados se muestran en la Tabla XVIII.The antispasmodic activity of the active ingredient used in the formulations was evaluated by studying its effect on contracted rat ileum, in 6-week-old Sprague Dawley rats weighing 300 to 350 grams. The rats were sacrificed and the ileum was removed for dissection. Each ileum was separated into four rings and mounted on 10 mL isolated organ vessels with modified Tyrode solution and allowed to stabilize for 1 hour, making changes to the solution every 15 minutes. Tyrode solution modified with 100 mM potassium chloride was added and contraction was induced. Subsequently, the active ingredient solution was added in increasing concentrations from 25 to 1 304 μg / mL. The relaxation was expressed as the percentage of decrease in the maximum tension obtained in the presence of the active ingredient and the results are shown in Table XVIII.
TABLA XVIII. Efecto antiespasmódico del ingrediente activo que se emplea en las formulaciones de la invención.TABLE XVIII Antispasmodic effect of the active ingredient that is used in the formulations of the invention.
Figure imgf000021_0001
Los resultados demostraron que las mezcla de ingredientes activos que se emplea en las formulaciones de la presente invención posee un efecto de relajación a una dosis media efectiva de 480 mg/Kg sobre íleon de cobayo, lo cual puede explicar su efecto antiespasmódico. Ejemplo 14
Figure imgf000021_0001
The results showed that the mixture of active ingredients used in the formulations of the present invention has a relaxation effect at an effective average dose of 480 mg / kg on guinea pig ileum, which may explain its antispasmodic effect. Example 14
Se evaluó la actividad anti-oxidante in υitro del ingrediente activo utilizado en las formulaciones antes descritas mediante la evaluación de su capacidad de auto-oxidación espontánea, inhibición de la peroxidación de fosfolípidos en homogenato de cerebro de rata y el sistema bleomicina-hierro, respectivamente, captación de radicales hidroxilo y de ácido hipocloroso. El ingrediente activo demostró tener actividad protectora frente a la peroxidación de fosfolípidos por vía enzimática en homogenato de cerebro de rata. Esta protección demostró ser dosis-dependiente y la dosis media protectora fue de 0,018 % (p/v) según se observa en la Tabla XIX.The in iteriter anti-oxidant activity of the active ingredient used in the formulations described above was evaluated by assessing its capacity for spontaneous self-oxidation, inhibition of phospholipid peroxidation in rat brain homogenate and the bleomycin-iron system, respectively. , uptake of hydroxyl radicals and hypochlorous acid. The active ingredient was shown to have protective activity against peroxidation of phospholipids enzymatically in rat brain homogenate. This protection proved to be dose-dependent and the average protective dose was 0.018% (w / v) as seen in Table XIX.
TABLA XIX. Inhibición de la autoxidación espontánea en fosfolípidos de cerebro de rata con el empleo del ingrediente activo de las formulaciones.TABLE XIX Inhibition of spontaneous autoxidation in rat brain phospholipids with the use of the active ingredient of the formulations.
Figure imgf000022_0001
Figure imgf000022_0001
En el sistema bleomicina-hierro se obtuvo igual efecto al descrito con anterioridad, pero con una concentración efectiva media ligeramente superiorIn the bleomycin-iron system, the same effect as described above was obtained, but with a slightly higher average effective concentration
(0,026 %), según se observa en la Tabla XX. Ambas concentraciones medias (0,018 y 0,026 %) son superiores a la necesaria para inhibir el proceso de peroxidación mediado sólo por enzimas.(0.026%), as seen in Table XX. Both mean concentrations (0.018 and 0.026%) are higher than necessary to inhibit the process of peroxidation mediated only by enzymes.
TABLA XX. Inhibición de la peroxidación de fosfolípidos en el sistema bleomicina-hierro con el empleo de la mezcla de ingredientes activos de las formulaciones de la invención.TABLE XX Inhibition of phospholipid peroxidation in the bleomycin-iron system with the use of the mixture of active ingredients of the formulations of the invention.
Figure imgf000023_0001
Figure imgf000023_0001
La capacidad de secuestro de radicales hidroxilo encontrada fue notablemente alta y se encontró que la concentración (p/v) en la que la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos exhibe una reducción del 50 % de radicales hidroxilos generados fue 0,011 %. Ello demuestra la elevada capacidad antioxidante del objeto de invención frente a una de las especies radicalarias de oxígeno que más frecuentemente se asocian con procesos de deterioro del organismo humano.The hydroxyl radical sequestration capacity found was remarkably high and it was found that the concentration (w / v) in which the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements exhibits a 50% reduction of hydroxyl radicals generated was 0.011 %. This demonstrates the high antioxidant capacity of the object of the invention against one of the radical oxygen species that is most frequently associated with processes of deterioration of the human organism.
La capacidad de secuestro de ácido hipocloroso que se encontró fue también notable, ya que la concentración (p/v) en la que se detectó la reducción del 50 % de la concentración de esta especie fue 0,04 %. Ello demuestra la elevada capacidad antioxidante del objeto de invención mediante la protección de la antiproteinasa alfa uno, la cual es degradada por el ácido hipocloroso.The sequestration capacity of hypochlorous acid that was found was also notable, since the concentration (w / v) at which the 50% reduction in the concentration of this species was detected was 0.04%. This demonstrates the high antioxidant capacity of the object of the invention by protecting the antiproteinase alpha one, which is degraded by hypochlorous acid.
Las propiedades antioxidantes descritas en el Ejemplo 14 para la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos objeto de invención no han sido descritas con anterioridad para ningún otro producto natural a niveles de concentración tan bajos, lo que demuestra su efectividad en la quimioprevención de eventos biológicos relacionados con el envejecimiento y patologías degenerativas que provocan un stress considerable en el organismo humano, lo cual se demostró en pacientes con neoplasias según los Ejemplos 7, 8 y 9. Estas propiedades anti-oxidantes, a su vez, se encuentran vinculadas a procesos fisiológicos relacionados con la inflamación y el dolor, descritas en los Ejemplos 10, 11, 12 y 13 lo que permite correlacionar las propiedades anti-inflamatoria, analgésica y antiespasmódica observadas con la elevada capacidad de inhibición de la peroxidación lipídica, autooxidación espontánea, secuestro de radicales hidroxilo y ácido hipocloroso, lo que confiere al objeto de invención características distintivas, por su alta eficacia, no reportadas con anterioridad para otro producto existente en el mercado The antioxidant properties described in Example 14 for the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements object of the invention have not been previously described for any other product. natural at such low concentration levels, demonstrating its effectiveness in the chemoprevention of biological events related to aging and degenerative pathologies that cause considerable stress in the human organism, which was demonstrated in patients with neoplasms according to Examples 7, 8 and 9. These anti-oxidant properties, in turn, are linked to physiological processes related to inflammation and pain, described in Examples 10, 11, 12 and 13 which allow correlating the anti-inflammatory, analgesic and antispasmodic observed with the high capacity of inhibition of lipid peroxidation, spontaneous autoxidation, sequestration of hydroxyl radicals and hypochlorous acid, which gives the object of the invention distinctive characteristics, due to its high efficiency, not previously reported for another product on the market.

Claims

REINVIDICACIONES 1. Mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenidos a partir de Mangifera indica L caracterizada porque su composición cualitativa y cuantitativa es la siguiente:CLAIMS 1. Mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained from Mangifera indicates L characterized in that its qualitative and quantitative composition is as follows:
Componente Contenido (%)Content Component (%)
Polifenoles 20-60Polyphenols 20-60
Mangiferina 10-20Mangiferin 10-20
Pentadecilfenol 5-10Pentadecylphenol 5-10
Octilfenol 5-10Octylphenol 5-10
Amentoflavona 10-20Amentoflavone 10-20
Terpenoides 10-40Terpenoids 10-40
Acido mangiferónico 15-30Mangiferonic acid 15-30
Beta-elemeno 5-10Beta-elemene 5-10
Alfa-guaieno 5-10Alpha-Guayanum 5-10
Aromandreno 5-10Aromandreno 5-10
Hinesol 1-5Hinesol 1-5
Cicloartanoles 1-5Cycloartanols 1-5
Ledol 1-5Ledol 1-5
Taraxerol 1-5Taraxerol 1-5
Esteroides 5-15Steroids 5-15
Gamma-sitoesterol 2-8Gamma-Sitosterol 2-8
Beta-sitoesterol 1-5Beta-Sitosterol 1-5
Campesterol 1-51-5 petrol
Daucoesterol 0,5-3Daucoesterol 0.5-3
Multifluorenona 0,5-3Multifluorenone 0.5-3
Ácidos grasos 1-51-5 fatty acids
Mirístico 0,1-3,0Myristic 0.1-3.0
Palmítico 35,0-45,0Palmitic 35.0-45.0
Linoleico 15,0-35,0Linoleic 15.0-35.0
Oleico 20,0-40,0Oleico 20.0-40.0
Esteárico 0,1-1,0 Eicosatrienoico 1,0-3,0 Microelementos 1-3Stearic 0.1-1.0 Eicosatrienoic 1.0-3.0 Microelements 1-3
Potasio 0,8-1,0Potassium 0.8-1.0
Calcio 0,2-0,40.2-0.4 calcium
Magnesio 0,1-0,20.1-0.2 Magnesium
Hierro 0,1-0,20.1-0.2 iron
Cobre Menor de 0,01Copper Less than 0.01
Zinc Menor de 0,01Zinc Less than 0.01
Selenio 0,03 - 0,08Selenium 0.03 - 0.08
2. Composición que contiene como principio activo la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenidos a partir de Mangifera indica L. de la reivinicación 1 y un excipiente apropiado, caracterizada porque la composición cualitativa y cuantitativa de dicha mezcla es la siguiente:2. Composition that contains as an active principle the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained from Mangifera indica L. of claim 1 and an appropriate excipient, characterized in that the qualitative and quantitative composition of said mixture is next:
Componente Contenido (%)Content Component (%)
Polifenoles 20-60Polyphenols 20-60
Mangiferina 10-20Mangiferin 10-20
Pentadecilfenol 5-10Pentadecylphenol 5-10
Octilfenol 5-10Octylphenol 5-10
Amentoflavona 10-20Amentoflavone 10-20
Terpenoides 10-40Terpenoids 10-40
Acido mangiferónico 15-30Mangiferonic acid 15-30
Beta-elemeno 5-10Beta-elemene 5-10
Alfa-guaieno 5-10Alpha-Guayanum 5-10
Aromandreno 5-10Aromandreno 5-10
Hinesol 1-5Hinesol 1-5
Cicloartanoles 1-5Cycloartanols 1-5
Ledol 1-5Ledol 1-5
Taraxerol 1-5 Esteroides 5-15Taraxerol 1-5 Steroids 5-15
Gamma-sitoesterol 2-8 Beta-sitoesterol 1-5 Campesterol 1-5 Daucoesterol 0,5-3 Multifluorenona 0,5-3 Ácidos grasos 1-5 Mirístico 0,1-3,0 Palmítico 35,0-45,0 Linoleico 15,0-35,0 Oleico 20,0-40,0 Esteárico 0,1-1,0 Eicosatrienoico 1,0-3,0 Microelementos 1-3 Potasio 0,8-1,0 Calcio 0,2 - 0,4 Magnesio 0,1-0,2 Hierro 0,1-0,2 Cobre Menor de 0,01 Zinc Menor de 0,01 Selenio 0,03 - 0,08Gamma-Sitosterol 2-8 Beta-Sitosterol 1-5 Campesterol 1-5 Daucoesterol 0.5-3 Multifluorenone 0.5-3 Fatty Acids 1-5 Myristic 0.1-3.0 Palmitic 35.0-45.0 Linoleic 15.0-35.0 Oleic 20.0-40.0 Stearic 0.1-1.0 Eicosatrienoic 1.0-3.0 Microelements 1-3 Potassium 0.8-1.0 Calcium 0.2-0, 4 Magnesium 0.1-0.2 Iron 0.1-0.2 Copper Less than 0.01 Zinc Less than 0.01 Selenium 0.03 - 0.08
3. Composición según la reivindicación 2 caracterizada porque para la formulación de una tableta revestida se utiliza una mezcla de estos componentes en una proporción del 45,0 al 55,0 % del ingrediente activo junto con rellenos, aglutinantes, desintegrantes, lubricantes, vehículos y demás excipientes farmacéuticos aceptables.3. Composition according to claim 2 characterized in that for the formulation of a coated tablet a mixture of these components is used in a proportion of 45.0 to 55.0% of the active ingredient together with fillers, binders, disintegrants, lubricants, vehicles and other acceptable pharmaceutical excipients.
4. Composición según la reivindicación 2 caracterizada porque para formulación de una suspensión saborizada se utiliza una mezcla de estos componentes en una proporción del 8,0 al 12,0 % del ingrediente activo junto con vehículos, estabilizantes y demás excipientes farmacéuticos aceptables. 4. Composition according to claim 2 characterized in that for the formulation of a flavored suspension a mixture of these components is used in a proportion of 8.0 to 12.0% of the active ingredient together with vehicles, stabilizers and other acceptable pharmaceutical excipients.
5. Composición según la reivindicación 2 caracterizada porque para formulación de una crema hidrófila se utiliza una mezcla de estos componentes en una proporción del 1,0 al 4,0 % del ingrediente activo junto con rellenos, vehículos, estabilizantes y demás excipientes farmacéuticos aceptables.5. Composition according to claim 2 characterized in that for the formulation of a hydrophilic cream a mixture of these components is used in a proportion of 1.0 to 4.0% of the active ingredient together with fillers, vehicles, stabilizers and other acceptable pharmaceutical excipients.
6. Composición según la reivindicación 2 caracterizada porque para formulación de un ungüento lipófilo se utiliza una mezcla de estos componentes en una proporción del 1,0 al 4,0 % del ingrediente activo junto con rellenos, vehículos y demás excipientes farmacéuticos aceptables. 6. Composition according to claim 2 characterized in that for the formulation of a lipophilic ointment a mixture of these components is used in a proportion of 1.0 to 4.0% of the active ingredient together with fillers, vehicles and other acceptable pharmaceutical excipients.
7. Uso de la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenidos a partir de Mangifera indica L de la reivindicación 1 para la fabricación de un medicamento útil en el tratamiento de pacientes inmunodeprimidos por enfermedades degenerativas en especial en pacientes con neoplasias, el cual se emplea a una dosis diaria entre 1 200 y 2 000 mg por vía oral y/o tópica.7. Use of the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained from Mangifera indica L of claim 1 for the manufacture of a medicament useful in the treatment of immunosuppressed patients due to degenerative diseases, especially in patients with neoplasms. , which is used at a daily dose between 1,200 and 2,000 mg orally and / or topically.
8. Uso de las formulaciones que contienen como ingrediente activo la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenida de Mangifera indica L. de la reivindicación 1 para la fabricación de productos anti-envejecimiento y quimiopreventivos de procesos degenerativos en el adulto una dosis diaria entre 1 000 y 1 200 mg por vía oral y/o tópica.8. Use of formulations containing as active ingredient the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained from Mangifera indica L. of claim 1 for the manufacture of anti-aging and chemopreventive products of degenerative processes in adults a daily dose between 1 000 and 1 200 mg orally and / or topically.
9. Uso de las formulaciones que contienen como ingrediente activo la mezcla de polifenoles, terpenoides, esteroides, ácidos grasos y microelementos obtenida de Mangifera indica L. de la reivindicación 1 para la fabricación de un suplemento dietético el cual se emplea a una dosis diaria entre 900 y 1 500 mg por vía oral o parenteral 9. Use of formulations containing as active ingredient the mixture of polyphenols, terpenoids, steroids, fatty acids and microelements obtained from Mangifera indica L. of claim 1 for the manufacture of a dietary supplement which is used at a daily dose between 900 and 1,500 mg orally or parenterally
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Publication number Priority date Publication date Assignee Title
FR2816211A1 (en) * 2000-11-08 2002-05-10 Brif Dietetic composition used for the relief of dryness of the mucous membranes containing prostaglandin precursors, antioxidants, brewers yeast enriched in minerals and optional softening agents
EP1216623A1 (en) * 2000-11-08 2002-06-26 Brif Dietary and/or cosmetic compositions for counteracting dryness of mucous membranes
WO2004035059A1 (en) * 2002-10-16 2004-04-29 Alan Fergusson Composition for the regulation of the human immune system and the prevention and treatment of diseases thereof
US8993551B2 (en) 2002-10-16 2015-03-31 Alan Ferguson Composition for the regulation of the human immune system and the prevention and treatment of diseases thereof
WO2006046257A2 (en) * 2004-10-27 2006-05-04 Geeta Pandurang Pawar An ayurvedic composition and process for preparing the composition to act as anti snake-venom
WO2006046257A3 (en) * 2004-10-27 2006-07-13 Geeta Pandurang Pawar An ayurvedic composition and process for preparing the composition to act as anti snake-venom
EP2700431A1 (en) * 2012-08-24 2014-02-26 AnalytiCon Discovery GmbH Plant extracts for modulating TRPV1 function
ES2464192A1 (en) * 2012-11-30 2014-05-30 Universidad De Cádiz Phenolic extracts of mangifera indica linn, procedure of obtaining and uses. (Machine-translation by Google Translate, not legally binding)
WO2015158836A1 (en) * 2014-04-16 2015-10-22 Vital Solutions Swiss Ag Mangifera indica as a sirtuin 1 activating agent
US10596212B2 (en) 2014-04-16 2020-03-24 Vital Solutions Swiss Ag Mangifera indica as a Sirtuin 1 activating agent

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CO5160343A1 (en) 2002-05-30

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