WO2019126896A1 - Phytotherapeutic powder formulation and use thereof in the event of a hypertensive crisis - Google Patents

Phytotherapeutic powder formulation and use thereof in the event of a hypertensive crisis Download PDF

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Publication number
WO2019126896A1
WO2019126896A1 PCT/CL2018/050153 CL2018050153W WO2019126896A1 WO 2019126896 A1 WO2019126896 A1 WO 2019126896A1 CL 2018050153 W CL2018050153 W CL 2018050153W WO 2019126896 A1 WO2019126896 A1 WO 2019126896A1
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Prior art keywords
lemon
formulation
blood pressure
phytotherapeutic
powder
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PCT/CL2018/050153
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Spanish (es)
French (fr)
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Marcia AVELLO LORCA
Jorge SANHUEZA SEPULVEDA
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Universidad de Concepción
Materias Primas Naturales Jorge Sanhueza Sepulveda Eirl
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Publication of WO2019126896A1 publication Critical patent/WO2019126896A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is presented as a solution to a problem in the health area, which is presented as a natural treatment for hypertensive crises.
  • Hypertension is a chronic disease of multifactorial etiology and corresponds to the persistent elevation of blood pressure over the reference limits. By convention it has been defined as such, when the systolic blood pressure is greater than or equal to 140 mmHg and / or a diastolic blood pressure greater than or equal to 90 mmHg 1 . There are no specific symptoms that suggest high blood pressure, occasionally patients report occipital headache, dizziness or heat, completely irrelevant and non-specific symptoms, so their diagnosis is usually casual.
  • this disease has a prevalence of 26.9% in the Chilean population and occurs mostly in patients 65 years and older. Of the total of people with hypertension, only 16.9% keep their blood pressure under control 3 .
  • the importance of arterial hypertension, as a public health problem, is due to the role it plays in cardiovascular morbidity and mortality, 4 in diseases such as coronary arteriosclerosis, heart failure, cerebrovascular accident, coronary insufficiency, congestive heart failure, chronic renal failure, among others, 5 being one of the main causes of death in Chile and the world 6 .
  • Self-care measures correspond to curative practices that are established in the family nucleus, either on their own initiative or that of some relatives of the patient, without the intervention of a health professional 7 and which are performed in the face of a disease or illness. Among these are mentioned: hygienic and / or dietary measures; self-medication with drugs and / or medicinal plants; ritual treatments or even not doing something 8 .
  • inulin has properties that may favor the reduction of total cholesterol, LDL, VLDL and triglycerides levels, as well as helping to balance insulin levels, 10 which can be used by diabetic and hypertensive people.
  • the pharmacological treatment of hypertension is a fundamental pillar in the prevention of cardiac, vascular and renal complications 11 .
  • monotherapy or a combination of drugs can be used.
  • the groups of antihypertensive drugs recommended by the MINSAL clinical guide and those most used in clinical practice are 12 : a) diuretics; b) angiotensin-converting enzyme (ACE) inhibitors; c) angiotensin II receptor antagonist (ARA-II); d) drugs that act on the nervous system; f) calcium channel blockers.
  • ACE angiotensin-converting enzyme
  • ARA-II angiotensin II receptor antagonist
  • Antihypertensive treatment must be complemented with non-pharmacological measures. These measures include the reduction of weight and consumption of sodium in the diet, reduction of alcohol consumption, increase in physical activity, a healthy diet, and the suspension of smoking. Its objectives are to reduce blood pressure, reduce the needs of antihypertensive drugs and / or increase their effectiveness, address other existing risk factors, and prevent associated cardiovascular disorders 13 .
  • captopril is used for sublingual administration, which has a fast and effective effect, nevertheless it is of intrahospitalar use.
  • Citrus lemon L. Burm. f. citrus tree belonging to the family of the Rutáceas and known by the vulgar name of lemon tree (lemon), is attributed a great variety of medicinal and nutritional properties.
  • the medicinal properties of lemon are due to its content in vitamin C and the variety of flavonoids it contains, since these compounds are involved in vahadas biological activities and have many functions related to health (antioxidants, anti-inflammatory, antiallergic, antiviral, antiproliferative, among others) 15 .
  • the producing regions correspond to the IV, V, VI and Metropolitan, the harvests concentrate between July and August, and the most important varieties for the national distribution are Fino 49 f Genoa, Eureka and Portugal.
  • flavonoids More than sixty flavonoids have been identified in the C. lemon species and most can be classified into three groups: flavanones, flavones and flavonols, the former being the most abundant and characteristic of this species as well as other phenolic compounds (phenolic acids) that 16 are present
  • flavonoids In coronary disease, the protective effects of flavonoids include, mainly, antithrombotic, anti-ischemic, antioxidant and vasodilator effects. 17 Studies //? Live studies have shown that flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress, and organ damage in hypertensive animals. On the other hand, some clinical studies have shown that foods rich in flavonoids can improve endothelial function in hypertensive patients and in ischemic heart disease. The effects of flavonoids on the relaxation of the arteries isolated from rats have been investigated in several studies, where they have been shown to cause vasodilation at physiological concentrations.
  • C lemon is the treatment of high blood pressure; In the literature reviewed, treatments are mentioned for several days for the prevention or for the reduction of blood pressure in the face of an increase. The quantities of lemons to be used and how they should be taken (diluted or pure) are vahadas and there is no single treatment. Until recently there was no mention of any clinical study that demonstrated this effect in our population, nor which one or which would be he or the components responsible for this action.
  • Figure 5 Average arterial pressure obtained with formulation 2.
  • Figure 6 Mean arterial pressure obtained with formulation 1.
  • the present technology corresponds to a herbal phytotherapeutic formulation for reconstitution in water or another aqueous base, comprising powdered lemon citrus juice and a polysaccharide, which can be selected from inulin, maltodextrin, dextrose, soluble fibers or dietary fibers.
  • This formulation comprises: a) 1.0-2.5 g of dried juice of C. lemon fruits; and b) 2.0-3.5 g of polysaccharide.
  • the amount of dried fruit juice of C. lemon is standardized and stable and corresponds to the amount needed to provide 0.5 - 50 mg of quercetin equivalent and / or 0.076 - 10 mg of ascorbic acid equivalent.
  • the polysaccharide gives dispersibility and wettability to the product.
  • This formulation besides contributing to the intestinal metabolism, helps to diminish the absorption of sugars and lipids, which favors cardiovascular health.
  • This product has a history of effectiveness and safety, which would contribute as a complement to the therapies for managing blood pressure increases, a public health problem with a high impact on cardiovascular morbidity and mortality in Chile and the world.
  • this formulation allows to observe an antihypertensive effect in patients with pressure increases, decrease of up to 10 mmHg, without exerting hypotensive effects because blood pressure does not decrease in normotensive patients. This could be useful as a measure of self-care, in the face of a situation in which there are no protocols to follow in emergency medical services.
  • Fruits of C. lemon were selected, coming from different regions of the country and varieties, according to the concentration of active principles. These fruits were subjected to drying procedures to establish the most stable presentation, and standardized in chemical markers that allow the dosage equivalent to the lemon juice of a common fruit.
  • the inulin Ferutafit® IQ was obtained from the Sensus supplier and managed according to its specifications.
  • EXAMPLE 1 Characterization of the juices and obtaining the formulation. Vegetal material
  • the fruits of C. lemon were obtained through fruit suppliers of the producing regions (IV, V, VI, and metropolitan).
  • Table 1 Characterization of the lemons used. mL juice / g average weight
  • the samples of lemon juice were diluted 20 times: 500 pL of each filtrate was taken and taken to 10.0 mL with distilled water. Then its absorbance at 280 nm was measured and its flavonoid content in quercetin equivalents was calculated with the
  • Population 5 is the one that concentrates the highest content of total flavonoids.
  • the phenolic compounds present in the lemon C juice were identified by high efficiency liquid chromatography (HPLC) in reverse phase, as described by Londo ⁇ o-Londo ⁇ o et al. 2012. Lemons from each population were washed and weighed. Then they were squeezed manually. The juice obtained was first filtered through cotton and after having subjected this filtering at 3000 revolutions per minute for 12 minutes the supernatant was filtered through a membrane with pore size of 0.45pm. This filtrate was placed in vials marked to be injected into the HPLC equipment.
  • HPLC high efficiency liquid chromatography
  • a Kromasil 100-5-C18 column of 4.6 x 250 mm and a mobile phase of Hexadecyltrimethylammonium bromide (HTAB) 5mM + potassium diacid phosphate (KH 2 P0 4 ) 50 mM were used as the stationary phase.
  • a flow of 1.2 mL / minute was used. The samples were read at 254 nm.
  • Lemon 5 501,264 28,302 28,30 Population 4 is the one that concentrates the highest content of ascorbic acid.
  • the juice of the selected C. lemon fruits was subjected to the following drying procedures in order to obtain it into the powder form.
  • the juice was frozen at -35 ° C in an ethanol bath and subjected to lyophilization.
  • the lyophilisate is stored in the freezer and protected from light until it is used.
  • inulin in the formulation as a coadjuvant for dispersing the powder in water.
  • inulin could enhance the beneficial properties of lemon juice in the control of hypertension and pathologies associated with it such as dyslipidemias and diabetes.
  • inulin as an auxiliary drying agent was as effective as maltodextrins, since good process performance and good physical characteristics (appearance, flow, aggregation) were obtained.
  • a Mini Spray DüchiBüchi B-290 was used, in which the lemon juice and the inulin juice were atomized. Once the dry powder was obtained, it was collected and stored in a desiccator, to reduce the absorption of moisture from the environment. In order to obtain the maximum performance of the process, the following parameters were studied: feed flow, air flow, inlet temperature (air), air aspiration, feed pressure.
  • Lemon juices have a high content of sugars and organic acids, which have low glass transition temperatures (Tg) and either spray drying or freeze-drying, there are problems of "stickiness” and high hygroscopicity of the products obtained.
  • the term "stickiness” refers to phenomena of particle-particle cohesion and particle-wall adhesion that present the obtained powders. As a consequence of these phenomena, we have low or no production yields.
  • a solution to the problem of stickiness is the use of drying aids.
  • Table 6 shows the results of the spray drying of the lemon juice, using as drying aids: inulin and / or maltodextrin, which were tested in different concentrations and proportions.
  • inlet temperature inlet t °
  • Table 6 Yield of powder production from lemon juice, obtained by the spray drying technique.
  • the juice powder was characterized and controlled by tests that demonstrate its quality and homogeneity.
  • the characterization studies were conducted in the formulation comprising lemon juice of the selected populations 4 and 5; and Inulin 15%; this formulation was dried by lyophilization.
  • the apparent density, technological parameter related to the powder flow was determined by measuring the volume occupied by a heavy amount of powder in a test tube, according to the modified pharmacopoeia methodology. The results were expressed in terms of bulk density (d g ) (table 6). The Carr index (I c ) and the Haussner index (I H ) were also determined, both parameters related to the dust flow.
  • the density is an important parameter, since it will allow us to know what amount of powder it is possible to introduce in a container with a determined volumetric capacity, for example a capsule or a sachet.
  • a container with a determined volumetric capacity for example a capsule or a sachet.
  • Ic and the I H both indirect measures of the flow, since it considers the friction between the particles.
  • IC values were obtained between 20-25, and I H values between 1.26-1.34, corresponding to a regular / acceptable flow.
  • the flow capacity of the powder was measured by determining the angle of repose, according to pharmacopoeial methodology. This is an indirect measure of the flow of a powder mass, which relates it to the adhesion forces between the particles and the packaging material or machinery, and the cohesion forces between particles (table 7).
  • solubility index in water, 1 g was weighed in a 250 mL Erlenmeyer flask containing 100 mL of distilled water. It was stirred until the whole sample was dissolved, then centrifuged at 3000 rpm for 10 min. A representative sample of 25 mL of the supernatant was taken and passed to Petri dishes. Finally, the sample was dried in an oven at 105 ° C for 5 h. Solubility (%) was calculated by weight difference. The solubility index of the powder was in the range of 88.9% and 97.0% (Table 8), that is, it corresponds to the percentage of solids that finally dissolved in the water. These values are quite satisfactory, since they ensure the dissolution of most of the components of the formulation.
  • the water absorption index test allows to evaluate the degree of hygroscopicity of the dry powder. To this end, 1 g of the dried product was placed in Petri dishes at 25 ° C in a desiccator containing a saturated solution of NaCl (75.4% humidity). relative), after 1 week the samples were weighed. The results are expressed as g of moisture per 100 g of dry solids (g / 100 g).
  • the phytodrug will have the following composition, presentation, and form of use.
  • FORMULA 1 (population 4)
  • the amount of each phytopharmaceutical component will be determined according to the following criteria:
  • Desiccated fruit juice of C. Limón ⁇ amount that gives the use of a sachet the dosage equivalent to the concentration of chemical markers in the lemon juice of a common fruit.
  • Inulin amount necessary to give the formulation dispersibility and wettability and complementary effects on the absorption of lipids and sugars.
  • the phytodrug will be standardized in the chemical markers determined for the dried juice and according to the methodology developed in point III.-.
  • C lemon is a fruit, it is subject to its active principles change, in concentration, according to the season of the year in which they are harvested, due to this a range of quercetin concentrations is established, which represents the total flavonoids present in juice of lemon.
  • the range determined in this study is: 0.5 - 50 mg of quercetin equivalent.
  • the same goes for ascorbic acid.
  • the range is: 0.076 - 10 mg of ascorbic acid equivalent.
  • Table 11 Release of active agents from C. lemon juice powder.
  • Quercetin concentrations increased by 28% during the study period. This may be explained by the characteristics of the quantification method (complex formation), which may be picking up sugars and phenolic groups of these. The physical-organoleptic and technological characteristics of Formulation 2 remained stable.
  • EXAMPLE 4 STUDY OF THE EFFECTIVENESS OF THE FORMULATION.
  • the phytopharmaceutical is reconstituted in water in such a way that allows the dosage equivalent to the concentration of the chemical markers in the lemon juice of a common fruit.
  • the sachets were dissolved in a glass of water and administered at the time the hypertensive crisis was detected.
  • the pressure was controlled at 0, 5, 10, 15, 30 and 60 minutes after the preparation was administered, obtaining the following results:
  • Table 13 Registry of arterial pressures obtained during two hypertensive crises after administration of the sachet with formulation 2.
  • Table 14 Record of arterial pressures obtained during two hypertensive crises after administration of the sachet with formulation 1.

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Abstract

The invention relates to a phytotherapeutic powder formulation comprising 1.0-2.5 g dried Citrus limon juice and 2.0-3.5 g polysaccharide, and to the use thereof to prepare a drug useful in the event of a hypertensive crisis and as a complement to therapies for managing increases in blood pressure, without exercising hypotensive effects, as blood pressure is not decreased in normotensive patients.

Description

UNA FORMULACION FITOTERAPEUTICA EN POLVO Y SU USO EN CASO DE  A PHYTOTHERAPEUTIC FORMULATION IN POWDER AND ITS USE IN CASE OF
CRISIS HIPERTENSIVA.  HYPERTENSIVE CRISIS.
Sector técnico Technical sector
La presente invención se presenta como una solución a un problema del área salud, el cual se presenta como un tratamiento natural para las crisis hipertensivas.  The present invention is presented as a solution to a problem in the health area, which is presented as a natural treatment for hypertensive crises.
Técnica anterior Previous technique
La hipertensión arterial (HTA) es una enfermedad crónica, de etiología multifactorial y que corresponde a la elevación persistente de la presión arterial sobre los límites referenciales. Por convención se ha definido como tal, cuando la presión arterial sistólica es mayor o igual a 140 mmHg y/o una presión arterial diastólica mayor o igual a 90 mmHg1. No hay síntomas específicos que sugieran hipertensión arterial, ocasionalmente los pacientes refieren cefalea occipital, mareos o calor, síntomas completamente irrelevantes y no específicos, por lo que su diagnóstico suele ser casual. Hypertension (HT) is a chronic disease of multifactorial etiology and corresponds to the persistent elevation of blood pressure over the reference limits. By convention it has been defined as such, when the systolic blood pressure is greater than or equal to 140 mmHg and / or a diastolic blood pressure greater than or equal to 90 mmHg 1 . There are no specific symptoms that suggest high blood pressure, occasionally patients report occipital headache, dizziness or heat, completely irrelevant and non-specific symptoms, so their diagnosis is usually casual.
Según la Encuesta Nacional de Salud del año 20102, esta enfermedad registra una prevalencia del 26,9% en la población chilena y se presenta mayormente en pacientes de 65 años y más. Del total de las personas con HTA sólo un 16,9% mantiene su presión arterial controlada3. La importancia de la hipertensión arterial, como problema de salud pública, se debe al rol que presenta en la morbilidad y mortalidad cardiovascular·4, en enfermedades tales como la arteriosclerosis coronaria, falla cardíaca, accidente vascular encefálico, insuficiencia coronaria, insuficiencia cardiaca congestiva, insuficiencia renal crónica, entre otras5, siendo una de las principales causas de muerte en Chile y el mundo6. According to the National Health Survey of 2010 2 , this disease has a prevalence of 26.9% in the Chilean population and occurs mostly in patients 65 years and older. Of the total of people with hypertension, only 16.9% keep their blood pressure under control 3 . The importance of arterial hypertension, as a public health problem, is due to the role it plays in cardiovascular morbidity and mortality, 4 in diseases such as coronary arteriosclerosis, heart failure, cerebrovascular accident, coronary insufficiency, congestive heart failure, chronic renal failure, among others, 5 being one of the main causes of death in Chile and the world 6 .
Entre los problemas de salud a los que puede verse enfrentado el paciente hipertenso, destacan las alzas de presión arterial, las que son inesperadas, espontáneas, y si no se controlan podrían conllevar a las crisis hipertensivas (presión arterial sistólica mayor o igual a 210 mmHg y una presión arterial diastólica mayor o igual a 120 mmHg), potencial mente peligrosas. Generalmente el paciente detecta las alzas de presión por síntomas vasculares y puede optar por acudir a algún sistema público de urgencia o realizar medidas de auto-atención. Among the health problems that can be faced by the hypertensive patient, highlights the rise in blood pressure, which are unexpected, spontaneous, and if not controlled could lead to hypertensive crises (systolic blood pressure greater than or equal to 210 mmHg and a diastolic blood pressure greater than or equal to 120 mmHg), potentially dangerous. Usually the patient detects pressure increases due to vascular symptoms and may choose to go to a public emergency system or take self-care measures.
Las medidas de auto-atención corresponden a prácticas curativas que se establecen en el núcleo familiar, ya sea por iniciativa propia o de algunos familiares del paciente, sin que medie un profesional de la salud7 y que se realizan ante un padecimiento o enfermedad. Dentro de éstas se mencionan: medidas higiénicas y/o dietéticas; automedicación con fármacos y/o plantas medicinales; tratamientos rituales o incluso no hacer algo8. Self-care measures correspond to curative practices that are established in the family nucleus, either on their own initiative or that of some relatives of the patient, without the intervention of a health professional 7 and which are performed in the face of a disease or illness. Among these are mentioned: hygienic and / or dietary measures; self-medication with drugs and / or medicinal plants; ritual treatments or even not doing something 8 .
Si bien no existen en la actualidad medidas de auto atención validadas, existen algunas que más bien caen dentro de la cultura popular, como es el uso de jugo de limón, el que por años ha sido ampliamente utilizado por la población para el manejo de las alzas de presión, sin embargo, este podría constituirse en un riesgo para el paciente debido principalmente a que no hay suficiente información en la literatura en relación al uso de limón con este fin y por tanto no existe una preparación estandarizada de este.  While there are currently no validated self-care measures, there are some that fall more within popular culture, such as the use of lemon juice, which for years has been widely used by the population for the management of pressure increases, however, this could be a risk for the patient, mainly because there is not enough information in the literature regarding the use of lemon for this purpose and therefore there is no standardized preparation of this.
Recientes estudios han mostrado que el jugo de limón es capaz de disminuir la presión arterial, cuando este se encuentra elevado en los pacientes hipertensos, sin influir en la presión arterial en pacientes normotensos9, pero es necesario estudios adicionales y en mayor población. Recent studies have shown that lemon juice is capable of lowering blood pressure, when it is elevated in hypertensive patients, without influencing blood pressure in normotensive patients, 9 but additional studies and a larger population are necessary.
Por otra parte se tiene que la hipertensión con la diabetes son enfermedades coexistentes en la población (entre un 40-60% de los diabéticos, sufren de hipertensión). En este contexto la inulina tiene propiedades que pueden favorecer la disminución de los niveles de colesterol total, LDL, VLDL y triglicéridos, además de ayuda a equilibrar los niveles de insulina10 pudiendo ser utilizada por las personas diabéticas e hipertensas. On the other hand it has that hypertension with diabetes are coexisting diseases in the population (between 40-60% of diabetics, suffer from hypertension). In this context, inulin has properties that may favor the reduction of total cholesterol, LDL, VLDL and triglycerides levels, as well as helping to balance insulin levels, 10 which can be used by diabetic and hypertensive people.
El tratamiento farmacológico de la HTA es un pilar fundamental en la prevención de complicaciones cardíacas, vasculares y renales11. Al inicio puede utilizarse monoterapia o una combinación de fármacos. Los grupos de fármacos antihipertensivos recomendados por la guía clínica del MINSAL y los más usados en la práctica clínica son12:a) diuréticos; b) inhibidores de la enzima convertidora de angiotensina (IECA); c) antagonista de los receptores de angiotensina II (ARA-II); d) fármacos que actúan sobre el sistema nervioso; f) bloqueadores de los canales de calcio. The pharmacological treatment of hypertension is a fundamental pillar in the prevention of cardiac, vascular and renal complications 11 . In the beginning, monotherapy or a combination of drugs can be used. The groups of antihypertensive drugs recommended by the MINSAL clinical guide and those most used in clinical practice are 12 : a) diuretics; b) angiotensin-converting enzyme (ACE) inhibitors; c) angiotensin II receptor antagonist (ARA-II); d) drugs that act on the nervous system; f) calcium channel blockers.
El tratamiento antihipertensivo debe ser complementado con medidas no farmacológicas. Estas medidas comprenden la reducción de peso y del consumo de sodio en la dieta, reducción del consumo de alcohol, aumento de la actividad física, una dieta saludable, y la suspensión del hábito de fumar. Sus objetivos son reducir la presión arterial, reducir las necesidades de fármacos antihipertensivos y/o aumentar su eficacia, abordar los demás factores de riesgo existentes, y prevenir los trastornos cardiovasculares asociados13. Antihypertensive treatment must be complemented with non-pharmacological measures. These measures include the reduction of weight and consumption of sodium in the diet, reduction of alcohol consumption, increase in physical activity, a healthy diet, and the suspension of smoking. Its objectives are to reduce blood pressure, reduce the needs of antihypertensive drugs and / or increase their effectiveness, address other existing risk factors, and prevent associated cardiovascular disorders 13 .
Como se mencionó anteriormente, existe un bajo porcentaje de pacientes hipertensos que se encuentran adecuadamente controlados1,4. El alto porcentaje de pacientes no controlados puede deberse a un cumplimiento deficiente de los tratamientos indicados o conductas inapropiadas. En cualquier caso el no control de la presión arterial favorece el desarrollo de las alzas de presión y las crisis hipertensivas, que pueden desembocar en complicaciones importantes hasta provocar la muerte del paciente. As mentioned previously, there is a low percentage of hypertensive patients who are adequately controlled 1,4 . The high percentage of uncontrolled patients may be due to poor compliance with the indicated treatments or inappropriate behaviors. In any case, the non-control of blood pressure favors the development of pressure increases and hypertensive crises, which can lead to significant complications until the death of the patient.
Para el manejo en crisis hipertensivas se utiliza el captopril de administración sublingual, el que tiene un efecto rápido y efectivo, no obstante es de uso intrahospitalario.  For the management of hypertensive crises, captopril is used for sublingual administration, which has a fast and effective effect, nevertheless it is of intrahospitalar use.
No existe un producto comercial que pueda ser usado en forma de autoatención para el manejo de las alzas de presión. Dentro de las medidas de auto- atención, a las que frecuentemente acceden los pacientes se mencionan la automedicación con fármacos y/o plantas medicinales las que frecuentemente por su mala administración no funcionan o bien tienen efectos colaterales indeseados.  There is no commercial product that can be used in the form of self-care for the handling of pressure increases. Within self-care measures, which are frequently accessed by patients, self-medication with drugs and / or medicinal plants is mentioned, which often due to poor administration do not work or have undesirable side effects.
Citrus limón L. Burm. f., árbol cítrico perteneciente a la familia de las Rutáceas y conocido con el nombre vulgar de limonero (limón), se le atribuyen una gran variedad de propiedades medicinales y nutricionales. Las propiedades medicinales del limón se deben a su contenido en vitamina C y a la variedad de flavonoides que contiene, ya que estos compuestos están implicados en vahadas actividades biológicas y tienen muchas funciones relacionadas con la salud (antioxidantes, antiinflamatorios, antialérgicos, antivirales, antiproliferativas, entre otras)15. En Chile, las regiones productoras corresponden a la IV, V, VI y Metropolitana, la cosechase concentra entre julio y agosto, y las variedades más importantes para la distribución nacional lo constituyen Fino 49f Génova, Eureka y Lisboa. Citrus lemon L. Burm. f., citrus tree belonging to the family of the Rutáceas and known by the vulgar name of lemon tree (lemon), is attributed a great variety of medicinal and nutritional properties. The medicinal properties of lemon are due to its content in vitamin C and the variety of flavonoids it contains, since these compounds are involved in vahadas biological activities and have many functions related to health (antioxidants, anti-inflammatory, antiallergic, antiviral, antiproliferative, among others) 15 . In Chile, the producing regions correspond to the IV, V, VI and Metropolitan, the harvests concentrate between July and August, and the most important varieties for the national distribution are Fino 49 f Genoa, Eureka and Lisbon.
Se han identificado más de sesenta flavonoides en la especie C. limón y la mayoría pueden ser clasificados en tres grupos: flavanonas, flavonas y flavonoles, siendo las primeras las más abundantes y características de esta especie además de otros compuestos fenólicos (ácidos fenólicos) que están presentes16. More than sixty flavonoids have been identified in the C. lemon species and most can be classified into three groups: flavanones, flavones and flavonols, the former being the most abundant and characteristic of this species as well as other phenolic compounds (phenolic acids) that 16 are present
Estudios epidemiológicos han mostrado que la ingesta regular de flavonoides se asocia con un menor riesgo de enfermedades cardiovasculares. En la enfermedad coronaria los efectos protectores de los flavonoides incluyen, principalmente efecto antitrombótico, antiisquémico, antioxidante y vasodilatador17. Estudios //? vivo han mostrado que los flavonoides previenen la disfunción endotelial y reducen la presión arterial, el estrés oxidativo, y el daño de órganos en animales hipertensos. Por otra parte, algunos estudios clínicos han mostrado que los alimentos ricos en flavonoides pueden mejorar la función endotelial en pacientes hipertensos y en enfermedad isquémica del corazón. Los efectos de los flavonoides en la relajación de las arterias aisladas de ratas se han investigado en diversos estudios, donde se ha mostrado que pueden causar vasodilatación en concentraciones fisiológicas. La relajación observada es en gran parte endotelio y óxido nítrico (NO) dependiente, aunque otros mecanismos también parecen estar involucrados1,4. En condiciones patológicas como la hipertensión y la aterosclerosis, hay una disfunción en el endotelio vascular con la consiguiente reducción en la liberación, la biodisponibilidad o la acción de los factores de relajación derivados del endotelio. Por lo tanto, se ha demostrado que la liberación o función de NO disminuye en pacientes hipertensos y en modelos animales de hipertensión; es por esto que el desarrollo de compuestos vasodilatadores, con la capacidad de restaurar los niveles de NO en el sistema vascular, podría contribuir al tratamiento de estas enfermedades cardiovasculares18. Epidemiological studies have shown that the regular intake of flavonoids is associated with a lower risk of cardiovascular diseases. In coronary disease, the protective effects of flavonoids include, mainly, antithrombotic, anti-ischemic, antioxidant and vasodilator effects. 17 Studies //? Live studies have shown that flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress, and organ damage in hypertensive animals. On the other hand, some clinical studies have shown that foods rich in flavonoids can improve endothelial function in hypertensive patients and in ischemic heart disease. The effects of flavonoids on the relaxation of the arteries isolated from rats have been investigated in several studies, where they have been shown to cause vasodilation at physiological concentrations. The observed relaxation is largely endothelium and nitric oxide (NO) -dependent, although other mechanisms also seem to be involved 1,4 . In pathological conditions such as hypertension and atherosclerosis, there is a dysfunction in the vascular endothelium with the consequent reduction in the release, bioavailability or action of relaxation factors derived from the endothelium. Therefore, it has been shown that the release or function of NO decreases in hypertensive patients and in animal models of hypertension; this is why the development of vasodilator compounds, with the ability to restore NO levels in the vascular system, could contribute to the treatment of these cardiovascular diseases 18 .
Entre uno de los tantos usos populares que se señalaron para C limón está el tratamiento de la hipertensión arterial; en la literatura revisada, se mencionan tratamientos durante varios días para la prevención o para la disminución de la presión arterial frente a un alza. Las cantidades de limones a usar y cómo se debe tomar (diluido o puro) son vahadas y no existe un tratamiento único. Hasta hace poco no se mencionaba algún estudio clínico que demostrara este efecto en nuestra población, ni cuál o cuáles serían él o los componentes responsables de esta acción. Among the many popular uses that were pointed out for C lemon is the treatment of high blood pressure; In the literature reviewed, treatments are mentioned for several days for the prevention or for the reduction of blood pressure in the face of an increase. The quantities of lemons to be used and how they should be taken (diluted or pure) are vahadas and there is no single treatment. Until recently there was no mention of any clinical study that demonstrated this effect in our population, nor which one or which would be he or the components responsible for this action.
A pesar de todos los antecedentes mencionados aún existe la necesidad de contar con tratamientos naturales para las crisis hipertensivas, que sean una herramienta para el manejo de alzas de presión con la que los pacientes se puedan asistir en una primera línea de acción. Despite all the aforementioned precedents, there is still a need to have natural treatments for hypertensive crises, which are a tool for managing pressure increases with which patients can be assisted in a first line of action.
Referencias  References
(1) Maicas, C., Lázaro, E., Alcalá, P., et al. Etiología y fisiopatología de la hipertensión arterial esencial. Monocardio 2003; 5 (3): 141-160.  (1) Maicas, C., Lázaro, E., Alcalá, P., et al. Etiology and pathophysiology of essential arterial hypertension. Monocardium 2003; 5 (3): 141-160.
(2) Ministerio de Salud, 2011. Encuesta Nacional de Salud Chile 2009-2010  (2) Ministry of Health, 2011. National Health Survey Chile 2009-2010
(3) Barragán, A. La práctica de la autoatención por fitoterapia en un grupo de familias mexicanas. Archivos en Medicina Familiar 2006; 8 (3): 155-162.  (3) Barragán, A. The practice of self-care for phytotherapy in a group of Mexican families. Archives in Family Medicine 2006; 8 (3): 155-162.
(4) Ministerio de Salud. Guía clínica de hipertensión arterial primaria o esencial en personas de 15 años y más. Santiago: MINSAL 2010.  (4) Ministry of Health. Clinical guide of primary or essential arterial hypertension in people of 15 years and more. Santiago: MINSAL 2010.
(5) Porth, C. Fisiopatología salud -enfermedad, un enfoque conceptual, séptima edición, Panamericana, 2006.  (5) Porth, C. Pathophysiology health -disease, a conceptual approach, seventh edition, Panamericana, 2006.
(6) Kunstmann, S. Epidemiología de la hipertensión arterial en Chile. Revista Médica de la Clínica /as Condes 2005; 16 (2): 44 - 47.  (6) Kunstmann, S. Epidemiology of arterial hypertension in Chile. Medical Journal of the Clinic / as Condes 2005; 16 (2): 44-47.
(7) Zehnder, C. Tratamiento de la hipertensión arterial. Revista Médica Clínica las Condes 2005; 16 (2): 83-91.  (7) Zehnder, C. Treatment of arterial hypertension. Revista Médica Clínica las Condes 2005; 16 (2): 83-91.
(8) Arganis, E. La autoatención en un grupo de ancianos con diabetes residentes en Iztapalapa D.F. Cuicuilco lOOS) 12 (33): 11-25.  (8) Arganis, E. Self-care in a group of elderly people with diabetes residing in Iztapalapa D.F. Cuicuilco lOOS) 12 (33): 11-25.
(9) Avello, M., Jofré, P., Pastene, E., Fernández, P. Use of Citrus limón L. (lemon) in treating blood pressure sudden rises. International Journal of Pharmacognosy and Phytochemical Research 2014; 6(3): 606-611.  (9) Avello, M., Jofré, P., Pastene, E., Fernandez, P. Use of lemon Citrus L. (lemon) in treating blood pressure sudden rises. International Journal of Pharmacognosy and Phytochemical Research 2014; 6 (3): 606-611.
(10) Balcázar-Muñoz, B, Martínez-Abundis, E, & González-Ortiz, M. (2003). Efecto de la administración oral de inulina sobre el perfil de lípidos y la sensibilidad a la insulina en individuos con obesidad y dislipidemia. Revista médica de Chile, 131(6), 597-604. (10) Balcázar-Muñoz, B, Martínez-Abundis, E, & González-Ortiz, M. (2003). Effect of oral administration of inulin on lipid profile and insulin sensitivity in individuals with obesity and dyslipidemia. Medical Journal of Chile, 131 (6), 597-604.
(11) Zehnder, C. Tratamiento de la hipertensión arterial. Revista Médica Clínica las Condes 2005; 16 (2): 83-91. (11) Zehnder, C. Treatment of arterial hypertension. Revista Médica Clínica las Condes 2005; 16 (2): 83-91.
(12) Ministerio de Salud. Guía clínica de hipertensión arterial primaria o esencial en personas de 15 años y más. Santiago: MINSAL 2010.  (12) Ministry of Health. Clinical guide of primary or essential arterial hypertension in people of 15 years and more. Santiago: MINSAL 2010.
(13) Cárdenas M., & Carrillo, C. Hipertensión arterial sistémica: diagnóstico, tratamiento y prevención. Boletín de Práctica Médica Efectiva 2006. (14) Barragán, A. La práctica de la autoatención por fitoterapia en un grupo de familias mexicanas. Archivos en Medicina Familiar 2006; 8 (3): 155-162. (13) Cárdenas M., & Carrillo, C. Systemic hypertension: diagnosis, treatment and prevention. Effective Medical Practice Bulletin 2006. (14) Barragán, A. The practice of self-care for phytotherapy in a group of Mexican families. Archives in Family Medicine 2006; 8 (3): 155-162.
(15) Del Rio, J.A. Fuster, M.D. Gómez, P., et ai. Citrus iimorr. a source of flavonoids of pharmaceutical interest. Food chemistry 200A,- 84 (3): 457-461.  (15) Del Rio, J.A. Fuster, M.D. Gómez, P., et ai. Citrus iimorr. a source of flavonoids of pharmaceutical interest. Food chemistry 200A, - 84 (3): 457-461.
(16) González, E., Domínguez, R., Moreno, D., et ai. Natural bioactive compounds of Citrus limón for food and health. Journal of Pharmaceutical and Biomedicai Anaiysis 2010; 51 (2): 327-345  (16) González, E., Domínguez, R., Moreno, D., et al. Natural bioactive compounds of lemon Citrus for food and health. Journal of Pharmaceutical and Biomedical Anaiysis 2010; 51 (2): 327-345
(17) Benavente-García, O. & Castillo, J. Update on uses and properties of Citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity. Journal of Agricultura! and Food Chemistry 2008; 56 ( 15): 6185-6205.  (17) Benavente-Garcia, O. & Castillo, J. Update on uses and properties of Citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity. Journal of Agriculture! and Food Chemistry 2008; 56 (15): 6185-6205.
(18) Lemos, V., Freitas, M., Muller, B., et ai. Dioclein, a new nitric oxide- and endothelium-dependent vasodilator flavonoid. European Journal of Pharmacology 1999; 386 (1): 41-46.  (18) Lemos, V., Freitas, M., Muller, B., et ai. Dioclein, a new nitric oxide- and endothelium-dependent vasodilator flavonoid. European Journal of Pharmacology 1999; 386 (1): 41-46.
Breve descripción de las figuras Brief description of the figures
Figura 1: Presión arterial Sistólica obtenida con la formulación 2.  Figure 1: Systolic blood pressure obtained with formulation 2.
Figura 2: Presión arterial diastólica obtenida con la formulación 2.  Figure 2: Diastolic blood pressure obtained with formulation 2.
Figura 3: Presión arterial Sistólica obtenida con la formulación 1.  Figure 3: Systolic blood pressure obtained with formulation 1.
Figura 4: Presión arterial diastólica obtenida con la formulación 1.  Figure 4: Diastolic blood pressure obtained with formulation 1.
Figura 5: Presión arterial media obtenida con la formulación 2.  Figure 5: Average arterial pressure obtained with formulation 2.
Figura 6: Presión arterial media obtenida con la formulación 1.  Figure 6: Mean arterial pressure obtained with formulation 1.
Divulgación de la invención Disclosure of the invention
La presente tecnología corresponde a una formulación fitoterapéutica en polvo para la reconstitución en agua u otra base acuosa, que comprende zumo pulverizado de Citrus limón y un polisacárido, el cual se puede seleccionar desde inulina, maltodextrina, dextrosa, fibras solubles o fibras dietarías.  The present technology corresponds to a herbal phytotherapeutic formulation for reconstitution in water or another aqueous base, comprising powdered lemon citrus juice and a polysaccharide, which can be selected from inulin, maltodextrin, dextrose, soluble fibers or dietary fibers.
Esta formulación comprende: a) 1,0 - 2,5 g de zumo desecado de frutos de C. limón ; y b) 2,0 - 3,5 g de polisacarido. La cantidad de zumo desecado de frutos de C. limón se encuentra estandarizado y estable y corresponde a la cantidad necesaria para aportar 0,5 - 50 mg de equivalente de quercetina y/o 0,076 - 10 mg de equivalente de ácido ascórbico. El polisacárido le otorga dispersabilidad y humectabilidad al producto. This formulation comprises: a) 1.0-2.5 g of dried juice of C. lemon fruits; and b) 2.0-3.5 g of polysaccharide. The amount of dried fruit juice of C. lemon is standardized and stable and corresponds to the amount needed to provide 0.5 - 50 mg of quercetin equivalent and / or 0.076 - 10 mg of ascorbic acid equivalent. The polysaccharide gives dispersibility and wettability to the product.
Esta formulación además de contribuir al metabolismo intestinal, ayuda a disminuir la absorción de azúcares y lípidos, por lo que favorece la salud cardiovascular.  This formulation, besides contributing to the intestinal metabolism, helps to diminish the absorption of sugars and lipids, which favors cardiovascular health.
Este producto presenta antecedentes de efectividad y seguridad, el cual contribuiría como complemento a las terapias de manejo de alzas de presión arterial, problema de salud pública con alto impacto en la morbilidad y mortalidad cardiovascular en Chile y el mundo. This product has a history of effectiveness and safety, which would contribute as a complement to the therapies for managing blood pressure increases, a public health problem with a high impact on cardiovascular morbidity and mortality in Chile and the world.
El uso de esta formulación permite observar un efecto antihipertensivo en pacientes con alzas de presión, disminución de hasta 10 mmHg, sin ejercer efectos hipotensivos porque no disminuye la presión arterial en pacientes normotensos. Esto podría ser útil como medida de auto-atención, frente a una situación en la cual no existen protocolos a seguir en los servicios médicos de urgencia. The use of this formulation allows to observe an antihypertensive effect in patients with pressure increases, decrease of up to 10 mmHg, without exerting hypotensive effects because blood pressure does not decrease in normotensive patients. This could be useful as a measure of self-care, in the face of a situation in which there are no protocols to follow in emergency medical services.
Se seleccionaron frutos de C. limón, provenientes de diversas regiones del país y variedades, de acuerdo a la concentración de principios activos. Estos frutos fueron sometidos a procedimientos de secado para establecer la presentación más estable, y estandarizada en marcadores químicos que permitan la dosificación equivalente al zumo de limón de un fruto corriente. La inulina (Frutafit® IQ) fue obtenida del proveedor Sensus y manejada según sus especificaciones.  Fruits of C. lemon were selected, coming from different regions of the country and varieties, according to the concentration of active principles. These fruits were subjected to drying procedures to establish the most stable presentation, and standardized in chemical markers that allow the dosage equivalent to the lemon juice of a common fruit. The inulin (Frutafit® IQ) was obtained from the Sensus supplier and managed according to its specifications.
Nuestra propuesta considera y cumple con las normas de calidad, estandarización y pruebas de efectividad en humanos.  Our proposal considers and complies with the standards of quality, standardization and human effectiveness tests.
Uno de los grandes problemas de calidad de los fitofármacos es la estandarización de las fuentes vegetales que los componen. Muchos de ellos carecen de este punto de calidad. La cuantificación de principios activos de extractos de plantas en el producto final, es otro punto que rara vez cumplen los fitofármacos y que ponen en duda su eficacia y seguridad. Además, para evaluar la completa efectividad y seguridad, los fitofármacos deben cumplir con estudios en su receptor final. En la tabla 1 se muestra un cuadro comparativo con los tratamientos utilizados hoy en día y como esta nueva formulación permite su uso en primera instancia en caso de crisis hipertensiva. One of the great problems of quality of phytopharmaceuticals is the standardization of the vegetal sources that compose them. Many of them lack this point of quality. The quantification of active principles of plant extracts in the final product is another point that phytopharmaceuticals rarely meet and that question their efficacy and safety. In addition, to evaluate the complete effectiveness and safety, phytodrugs must comply with studies in their final recipient. Table 1 shows a comparative table with the treatments used today and how this new formulation allows its use in the first instance in case of hypertensive crisis.
Tabla 1: comparación con los fármacos utilizados hoy en día.  Table 1: comparison with the drugs used today.
Fármaco terapia Fármaco crisis FormulaciónDrug therapy Drug crisis Formulation
Ejemplos Anfibol® Nebivolol Examples Anfibol® Nebivolol
Captopril sublingual  Captopril sublingual
Losartán  Losartán
Antihipertensivo en Antihypertensive in
Funcionalidad Antihipertensivo uso Antihipertensivo de Functionality Antihypertensive use Antihypertensive of
alzas de presión crónico urgencia  urges chronic pressure urgency
arterial arterial
USO Uso en hipertensión Uso en crisis Uso en alzas de controlada hipertensivas presión arterial U SO Use in hypertension Use in crisis Use in controlled hypertensive high blood pressure
Disponible en el Available in
Disponibilidad Disponible en el hogar Uso i ntra hospitalario Availability Available in the home Use in the hospital
hogar Cabe destacar que los fármacos destinados a crisis hipertensivas son de uso intrahospitalario y no de manejo en casa S.O.S como lo es nuestra formulación.  Home It should be noted that drugs intended for hypertensive crises are for intrahospital use and not for home management S.O.S as is our formulation.
EJEMPLOS DE APLICACIÓNEXAMPLES OF APPLICATION
EJEMPLO 1: Caracterización de los zumos y obtención de la formulación. Material vegetal EXAMPLE 1: Characterization of the juices and obtaining the formulation. Vegetal material
Los frutos de C. limón fueron obtenidos a través de proveedores frutícolas de las regiones productoras (IV, V, VI, y metropolitana).  The fruits of C. lemon were obtained through fruit suppliers of the producing regions (IV, V, VI, and metropolitan).
Para la obtención del zumo de frutos de C. limón, se lavaron y exprimieron de manera manual, luego se filtró directamente a un vaso de precipitado, por algodón, para remover la pulpa. El zumo obtenido se centrifugó por 6 minutos a 10000 rpm a temperatura ambiente. El sobrenadante se removió con micropipeta y se sometió a filtración al vacío con una membrana de tamaño de poro de 0,45 pm y que está acoplado a una bomba de vacío. Este zumo filtrado se almacena a 4°C, y protegido de la luz hasta el momento de su utilización. Para simplificar, se denominó a las poblaciones "limón 1", "limón 2", hasta llegar a "limón 5", en la tabla 1 se muestra su caracterización: To obtain the juice of lemon fruits, they were washed and squeezed manually, then filtered directly into a beaker, by cotton, to remove the pulp. The obtained juice was centrifuged for 6 minutes at 10,000 rpm at room temperature. The supernatant was removed with a micropipette and subjected to vacuum filtration with a pore size membrane of 0.45 μm and which is coupled to a vacuum pump. This filtered juice is stored at 4 ° C, and protected from light until it is used. For simplicity, the populations were named "lemon 1", "lemon 2", until reaching "lemon 5", in table 1 their characterization is shown:
Tabla 1: Caracterización de los limones utilizados. mL zumo / g peso promedioTable 1: Characterization of the lemons used. mL juice / g average weight
Origen Origin
limón limón  lemon lemon
Limón 1 Agroreina, Melipilla 0,174 ml/g 111,05 g  Lemon 1 Agrorein, Melipilla 0,174 ml / g 111,05 g
Limón 2 Santa María, V región 0,229 ml/g 90,81 g  Lemon 2 Santa María, V region 0.229 ml / g 90.81 g
Santa Eliza,  Santa Eliza,
Limón 3 0,253 ml/g 94,68 g  Lemon 3 0.253 ml / g 94.68 g
Aconcagua  Aconcagua
Los Maitenes, IV  The Maitenes, IV
Limón 4 0,192 ml/g 117,83 g  Lemon 4 0.192 ml / g 117.83 g
región  region
Agrícola Randu,  Agricultural Randu,
Limón 5 0,165 ml/g 84,10 g  Lemon 5 0.165 ml / g 84.10 g
Santiago  Santiago
Se decide llevar a cabo el estudio piloto con el zumo de los limones de las poblaciones cuatro y cinco ("limón 4 y 5") por sus contenidos elevados de ácido ascórbico y de flavonoides totales (estandarizados en equivalentes de quercetina), respectivamente (tabla 2). It was decided to carry out the pilot study with juice of the lemons of populations four and five ("lemon 4 and 5") for their high contents of ascorbic acid and total flavonoids (standardized in equivalents of quercetin), respectively (table two).
Tabla 2. Concentraciones de equivalentes de quercetina y ácido ascórbico en las respectivas poblaciones seleccionadas (n=2).  Table 2. Concentrations of equivalents of quercetin and ascorbic acid in the respective selected populations (n = 2).
pg eq quercetina/mL pg ác.ascórbico /mL Población 4 281,140 76,54  pg quercetin / mL pg acc.ascorbic / mL Population 4 281,140 76.54
Población 5 541,888 28,30  Population 5 541,888 28,30
Identificación y cuantificación de principios activos. Identification and quantification of active principles.
Se desarrollaron y validaron métodos analíticos para la identificación y cuantificación de los principios activos característicos de frutos, estandarizados morfológicamente según variedades. Analytical methods were developed and validated for the identification and quantification of the characteristic active ingredients of fruits, morphologically standardized according to varieties.
Espectrofotometría  Spectrophotometry
Para la determinación de flavonoides totales se utilizó el método descrito por Jía et al. (1999). Para esto se utiliza como estándar quercetina, con la cual se preparó una curva de calibración. Los resultados se expresan en equivalentes de quercetina (EQ/mL) (tabla 3).  For the determination of total flavonoids, the method described by Jía et al. (1999). For this, quercetin is used as standard, with which a calibration curve was prepared. The results are expressed in equivalents of quercetin (EQ / mL) (Table 3).
Las muestras de zumo de limón se diluyeron 20 veces: se tomaron 500 pL de cada filtrado y se llevaron a 10.0 mL con agua destilada. Luego se midió su absorbancia a 280 nm y se calculó su contenido de flavonoides en equivalentes de quercetina con el The samples of lemon juice were diluted 20 times: 500 pL of each filtrate was taken and taken to 10.0 mL with distilled water. Then its absorbance at 280 nm was measured and its flavonoid content in quercetin equivalents was calculated with the
£ de la quercetina a esta longitud de onda. Tabla 3. Cuantificación de flavonoides totales expresados en equivalentes de quercetina en zumo de limón. £ of quercetin at this wavelength. Table 3. Quantification of total flavonoids expressed in equivalents of quercetin in lemon juice.
pg eq/mL pg eq / mL
Absorbancia 1 pg eq/mL Absorbancia 2 pg eq/mL Absorbance 1 pg eq / mL Absorbance 2 pg eq / mL
promedio average
Limón 1 0,544 336,898 0,557 345,266 341,082Lemon 1 0,544 336,898 0,557 345,266 341,082
Limón 2 0,706 437,688 0,724 449,093 443,390Lemon 2 0,706 437,688 0,724 449,093 443,390
Limón 3 0,671 416,055 0,672 416,364 416,210Lemon 3 0,671 416,055 0,672 416,364 416,210
Limón 4 0,457 283,093 0,450 279,188 281,140Lemon 4 0,457 283,093 0,450 279,188 281,140
Limón 5 0,870 539,470 0,878 544,305 541,888 Lemon 5 0,870 539,470 0,878 544,305 541,888
La población 5 es la que concentra el mayor contenido de flavonoides totales. Population 5 is the one that concentrates the highest content of total flavonoids.
Determinación de ácido ascórbico Determination of ascorbic acid
Los compuestos fenólicos presentes en el zumo de C limón, se identificaron por cromatografía líquida de alta eficiencia (HPLC) en fase reversa, según describe Londoño-Londoño et al. 2012. Se lavaron y pesaron limones de cada población. Luego se procedió a exprimirlos manualmente. El jugo obtenido se filtró primero a través de un algodón y después de haber sometido este filtrado a 3000 revoluciones por minuto por 12 minutos el sobrenadante se filtró por membrana con tamaño de poro de 0,45pm. Este filtrado se dispuso en viales marcados para ser inyectados en el equipo HPLC. Se utilizó como fase estacionaria una columna Kromasil 100-5-C18 de 4.6 x 250 mm y una fase móvil de Hexadeciltrimetilamonio bromuro (HTAB) 5mM+ Fosfato diácido de potasio (KH2P04) 50 mM. Se usó un flujo de 1.2 mL/ minuto. Las muestras se leyeron a 254 nm. The phenolic compounds present in the lemon C juice were identified by high efficiency liquid chromatography (HPLC) in reverse phase, as described by Londoño-Londoño et al. 2012. Lemons from each population were washed and weighed. Then they were squeezed manually. The juice obtained was first filtered through cotton and after having subjected this filtering at 3000 revolutions per minute for 12 minutes the supernatant was filtered through a membrane with pore size of 0.45pm. This filtrate was placed in vials marked to be injected into the HPLC equipment. A Kromasil 100-5-C18 column of 4.6 x 250 mm and a mobile phase of Hexadecyltrimethylammonium bromide (HTAB) 5mM + potassium diacid phosphate (KH 2 P0 4 ) 50 mM were used as the stationary phase. A flow of 1.2 mL / minute was used. The samples were read at 254 nm.
Tabla 4. Cuantificación de ácido ascórbico en zumo de limón. Table 4. Quantification of ascorbic acid in lemon juice.
AA (pg/mL) AA (pg / mL)
Muestra Área 1 Área 2 AA (pg/mL) 1 AA (pg/mL) 2 Sample Area 1 Area 2 AA (pg / mL) 1 AA (pg / mL) 2
promedio average
Limón 1 569,803 489,604 32,243 27,632 29,94Lemon 1 569,803 489,604 32,243 27,632 29.94
Limón 2 739,806 939,336 42,016 53,488 47,75Lemon 2 739,806 939,336 42,016 53,488 47.75
Limón 3 459,038 25,875 25,87Lemon 3 459,038 25,875 25.87
Limón 4 1473,822 1206,719 84,216 68,860 76,54Lemon 4 1473,822 1206,719 84,216 68,860 76.54
Limón 5 501,264 28,302 28,30 La población 4 es la que concentra el mayor contenido de ácido ascórbico. Lemon 5 501,264 28,302 28,30 Population 4 is the one that concentrates the highest content of ascorbic acid.
Secado por Liofilización Drying by Lyophilization
El zumo de los frutos de C. limón seleccionados fue sometidos a los siguientes procedimientos de secado con el fin de obtenerlo a la forma de polvo.  The juice of the selected C. lemon fruits was subjected to the following drying procedures in order to obtain it into the powder form.
El zumo se congeló a una temperatura -35°C en un baño de etanol y se sometió a liofilización. El liofilizado se almaceno en el congelador y protegido de la luz hasta el momento de su utilización.  The juice was frozen at -35 ° C in an ethanol bath and subjected to lyophilization. The lyophilisate is stored in the freezer and protected from light until it is used.
Al igual que en el proceso de secado por atomización, en la liofilización fue necesario incorporar un ayudante de secado, ya que no fue posible obtener un polvo cuando el zumo puro fue sometido al proceso de liofilización. Para este fin se utilizó: (1) inulina (15%), (2) maltodextrina (15%) y (3) mezcla 1:2 de inulina/maltodextrina (10%). En la tabla 5 se presentan los resultados de la liofilización.  As in the spray drying process, in the lyophilization it was necessary to incorporate a drying aid, since it was not possible to obtain a powder when the pure juice was subjected to the lyophilization process. To this end, we used: (1) inulin (15%), (2) maltodextrin (15%) and (3) 1: 2 mixture of inulin / maltodextrin (10%). Table 5 shows the results of lyophilization.
Tabla 5. Rendimiento de producción de polvo a partir de zumo de limón, obtenido por la técnica de liofilización. Table 5. Yield of powder production from lemon juice, obtained by the lyophilization technique.
g solido g solido g solidos Porcentaje g solid solid g solid g Percentage
Balón
Figure imgf000012_0001
zumo ~ .. . , . . Ball
Figure imgf000012_0001
juice ~ .. ,. .
_ añadidos pre-liof pos-liof recuperación _ added pre-liof post-liof recovery
Inu 15% 10 1,5 2,457 2,3173 94,31% MD 15% 10 1,5 2,457 2,3044 93,79%Inu 15% 10 1,5 2,457 2,3173 94.31% MD 15% 10 1,5 2,457 2,3044 93.79%
Inu/MD 1:2 10% 10 1 1,957 1,8973 96,95% Inu / MD 1: 2 10% 10 1 1,957 1,8973 96.95%
En todos los casos se obtuvo un alto rendimiento (> 93%), por lo que se seleccionó esta técnica de secado para la obtención del polvo de zumo de limón. De las tres formulaciones ensayadas se seleccionó la formulación que contiene Inulina 15%, por las siguientes razones: In all cases a high yield was obtained (> 93%), so this drying technique was selected to obtain the lemon juice powder. Of the three formulations tested, the formulation containing Inulin 15% was selected, for the following reasons:
1. Inicialmente se pensó incorporar inulina en la formulación como coadyuvante de dispersión del polvo en agua. Además, de aprovechar que la inulina podría potenciar las propiedades beneficiosas del zumo de limón en el control de la hipertensión y patologías asociadas a esta como son dislipidemias y diabetes. 2. La adición de inulina como excipiente ayudante de secado fue tan eficaz como las maltodextrinas, ya que se obtuvo un buen rendimiento de proceso, y buenas características físicas (aspecto, flujo, agregación). 1. Initially it was thought to incorporate inulin in the formulation as a coadjuvant for dispersing the powder in water. In addition, to take advantage of the fact that inulin could enhance the beneficial properties of lemon juice in the control of hypertension and pathologies associated with it such as dyslipidemias and diabetes. 2. The addition of inulin as an auxiliary drying agent was as effective as maltodextrins, since good process performance and good physical characteristics (appearance, flow, aggregation) were obtained.
Secado por atomización (spray dring) Spray drying (spray dring)
Se utilizó un equipo Mini Spray DryerBüchi B-290, en el cual se atomizó el zumo de frutos de C. limón y la inulina. Una vez obtenido el polvo seco, este fue recolectado y almacenado en un desecador, para reducir la absorción de humedad del ambiente. Con el objetivo de obtener los máximos rendimientos de proceso, se estudiaron los siguientes parámetros: flujo de alimentación, flujo de aire, temperatura de entrada (aire), aspiración del aire, presión de alimentación.  A Mini Spray DüchiBüchi B-290 was used, in which the lemon juice and the inulin juice were atomized. Once the dry powder was obtained, it was collected and stored in a desiccator, to reduce the absorption of moisture from the environment. In order to obtain the maximum performance of the process, the following parameters were studied: feed flow, air flow, inlet temperature (air), air aspiration, feed pressure.
Los zumos de limón presentan un elevado contenido de azúcares y ácidos orgánicos, los cuales tienen temperaturas de transición vitrea (Tg) bajas y ya sea con el secado por atomización o bien por el secado por liofilización, se producen problemas de "pegajosidad" y de elevada higroscopicidad de los productos obtenidos. El término de pegajosidad se refiere a fenómenos de cohesión partícula-partícula y de adhesión partícula-pared que presentan los polvos obtenidos. Como consecuencia de estos fenómenos, tenemos bajos o nulos rendimientos de producción. Una solución al problema de la pegajosidad es la utilización de productos ayudantes de secado. Lemon juices have a high content of sugars and organic acids, which have low glass transition temperatures (Tg) and either spray drying or freeze-drying, there are problems of "stickiness" and high hygroscopicity of the products obtained. The term "stickiness" refers to phenomena of particle-particle cohesion and particle-wall adhesion that present the obtained powders. As a consequence of these phenomena, we have low or no production yields. A solution to the problem of stickiness is the use of drying aids.
En la tabla 6 se presentan los resultados del secado por atomización del zumo de limón, utilizando como ayudantes de secado: inulina y/o maltodextrina, las que se ensayaron en diferentes concentraciones y proporciones. Además, se estudió el efecto de la temperatura de entrada (inlet t°) en el rendimiento de producción del polvo, manteniendo constantes: la velocidad de alimentación del equipo, el flujo de aire, la presión de alimentación y la aspiración. Tabla 6. Rendimiento de producción de polvo a partir de zumo de limón, obtenido por la técnica de secado por atomización.
Figure imgf000014_0001
Table 6 shows the results of the spray drying of the lemon juice, using as drying aids: inulin and / or maltodextrin, which were tested in different concentrations and proportions. In addition, the effect of the inlet temperature (inlet t °) on the dust production performance was studied, keeping constant: the feeding speed of the equipment, the air flow, the feeding pressure and the suction. Table 6. Yield of powder production from lemon juice, obtained by the spray drying technique.
Figure imgf000014_0001
Concentración Inlet g sólidos g polvo %  Concentration Inlet g solids g powder%
volumen sólidos sólidos  solid solids volume
(% p/v) (°C) añadidos recuperado recuperación zumo total  (% p / v) (° C) added recovered full juice recovery
MD 10% 140 10,023 100 mL 9,570 19,593 11,356 58,0 MD 10% 140 10,023 100 mL 9,570 19,593 11,356
MD 15% 140 7,510 50 mL 4,785 12,295 7,083 57.6MD 15% 140 7,510 50 mL 4,785 12,295 7,083 57.6
MD 20% 140 10,017 50 mL 4,785 14,802 8,8235 59.6MD 20% 140 10,017 50 mL 4,785 14,802 8.8235 59.6
Inu 10% 140 5,055 50 mL 4,785 9,840 5,1458 52.3Inu 10% 140 5,055 50 mL 4,785 9,840 5,1458 52.3
Inu 15% 140 7,523 50 mL 4,785 12,308 6,413 52.2Inu 15% 140 7,523 50 mL 4,785 12,308 6,413 52.2
Inu 20% 140 10,024 46,5 mL 4,785 14,474 7,2093 48.7 Inu/MD (1 :1) 10% 140 5,074 50 mL 4,785 9,859 4,764 48.4 Inu/MD (2:1) 15% 140 7,570 50 mL 4,785 12,355 6,8283 55.3 Inu/MD (1 :1) 10% 120 5,034 50 mL 4,785 9,819 4,988 50.8 Inu/MD (1 :1) 10% 130 5,062 50 mL 4,785 9,847 5,594 56.8 Inu/MD (1 :1) 10% 150 5,033 50 mL 4,785 9,818 5,759 58.7 Inu/MD (2:1) 10% 140 5,030 50 mL 4,785 9,815 5,562 56.7 Inu/MD (1 :2) 10% 140 5,057 50 mL 4,785 9,842 5,611 57,0 Inu/MD (1 :2) 15% 140 7,567 50 mL 4,785 12,352 6,303 51,03 Inu 20% 140 10,024 46.5 mL 4,785 14,474 7,2093 48.7 Inu / MD (1: 1) 10% 140 5,074 50 mL 4,785 9,859 4,764 48.4 Inu / MD (2: 1) 15% 140 7,570 50 mL 4,785 12,355 6 , 8283 55.3 Inu / MD (1: 1) 10% 120 5,034 50 mL 4,785 9,819 4,988 50.8 Inu / MD (1: 1) 10% 130 5,062 50 mL 4,785 9,847 5,594 56.8 Inu / MD (1: 1) 10% 150 5,033 50 mL 4,785 9,818 5,759 58.7 Inu / MD (2: 1) 10% 140 5,030 50 mL 4,785 9,815 5,562 56.7 Inu / MD (1: 2) 10% 140 5,057 50 mL 4,785 9,842 5,611 57.0 Inu / MD (1 : 2) 15% 140 7,567 50 mL 4,785 12,352 6,303 51.03
De todas las formulaciones ensayadas, se seleccionaron aquellas que presentaron altos rendimientos de producción y buenas características de físicas (aspecto del polvo, flujo, agregación, etc.). Of all the formulations tested, those that showed high production yields and good physical characteristics (powder appearance, flow, aggregation, etc.) were selected.
- Inulina 15% - 15% Inulin
- Maltodextrina 15%  - Maltodextrin 15%
- Inulina/Maltodextrina 1:2 10%  - Inulin / Maltodextrin 1: 2 10%
Posteriormente, estas tres formulaciones seleccionadas, fueron secadas mediante liofilización, con fin de comparar ambos métodos de secado. Subsequently, these three selected formulations were dried by lyophilization, in order to compare both drying methods.
Caracterización y Control del Zumo en Polvo Characterization and Control of Powdered Juice
El zumo en polvo fue caracterizado y controlado mediante ensayos que demuestren su calidad y homogeneidad. Los estudios de caracterización fueron realizados en la formulación que comprende zumo de limón de las poblaciones seleccionadas 4 y 5; e Inulina 15%; esta formulación fue secada mediante liofilización. The juice powder was characterized and controlled by tests that demonstrate its quality and homogeneity. The characterization studies were conducted in the formulation comprising lemon juice of the selected populations 4 and 5; and Inulin 15%; this formulation was dried by lyophilization.
La densidad aparente, parámetro tecnológico relacionado con el flujo del polvo, se determinó midiendo el volumen que ocupa una cantidad pesada de polvo en una probeta, según metodología de farmacopea modificada. Los resultados fueron expresados en términos de densidad granel (dg) (tabla 6). También se determinó el índice de Carr (Ic) y el índice de Haussner (IH), ambos parámetros relacionados con el flujo del polvo. The apparent density, technological parameter related to the powder flow, was determined by measuring the volume occupied by a heavy amount of powder in a test tube, according to the modified pharmacopoeia methodology. The results were expressed in terms of bulk density (d g ) (table 6). The Carr index (I c ) and the Haussner index (I H ) were also determined, both parameters related to the dust flow.
Tabla 6. Valores de densidad granel, índice de Carr e índice de Haussner para polvo de zumo de limón obtenido por liofilización (n=3).  Table 6. Bulk density values, Carr index and Haussner index for lemon juice powder obtained by lyophilization (n = 3).
Muestra dg (g/mL) Ic IH Sample d g (g / mL) I c IH
Limón 4 0,4351 20,64 1,26 Limón 5 0,4158 21,09 1,27  Lemon 4 0.4351 20.64 1.26 Lemon 5 0.4158 21.09 1.27
La densidad es un parámetro importante, ya que nos permitirá saber qué cantidad de polvo es posible introducir en un envase con una capacidad volumétrica determinada, por ejemplo una cápsula o un sachet. Además, con el dato de la densidad granel y la densidad compactada es posible obtener los Ic y el IH, ambos medidas indirectas del flujo, ya que considera la fricción entre las partículas. En las muestras analizadas se obtuvieron valores de IC entre 20-25, y valores de IH entre 1,26-1,34, que corresponde a un flujo regular/aceptable. The density is an important parameter, since it will allow us to know what amount of powder it is possible to introduce in a container with a determined volumetric capacity, for example a capsule or a sachet. In addition, with the data of the bulk density and the compacted density it is possible to obtain the Ic and the I H , both indirect measures of the flow, since it considers the friction between the particles. In the samples analyzed, IC values were obtained between 20-25, and I H values between 1.26-1.34, corresponding to a regular / acceptable flow.
La capacidad de flujo del polvo fue medida mediante la determinación del ángulo de reposo, de acuerdo a metodología farmacopeica. Esta es una medida indirecta del flujo de una masa de polvos, que lo relaciona con las fuerzas de adhesión entre las partículas y el material de envases o maquinaria, y las fuerzas de cohesión entre partículas (tabla 7).  The flow capacity of the powder was measured by determining the angle of repose, according to pharmacopoeial methodology. This is an indirect measure of the flow of a powder mass, which relates it to the adhesion forces between the particles and the packaging material or machinery, and the cohesion forces between particles (table 7).
Tabla 7. Valores de ángulo de reposo para polvo de zumo de limón obtenido por liofilización (n=3).  Table 7. Rest angle values for lemon juice powder obtained by lyophilization (n = 3).
Muestra Ángulo reposo Sample Angle rest
Limón 4 36,5°  Lemon 4 36.5 °
Limón 5 38,8° En las muestras analizadas, los valores de ángulo de reposo indican un flujo regular/aceptable, por lo que están en concordancia con los resultados de Ic y IH. ES posible que el contenido de humedad del polvo sea un factor importante en el grado de cohesividad de este y que afecta finalmente sus propiedades de flujo. Lemon 5 38.8 ° In the samples analyzed, the resting angle values indicate a regular / acceptable flow, so they are in accordance with the results of Ic and IH. It is possible that the moisture content of the powder is an important factor in the degree of cohesiveness of the latter and that it ultimately affects its flow properties.
Tanto en el ensayo de índice de solubilidad como en los ensayos de índice de absorción de agua y humedad, además de la formulación seleccionada (Inu 15% obtenida por liofilización), se evaluaron las formulaciones Inu 15% obtenida por spray dried, MD 15% obtenida por spray dried y Inu/MD (1:2) 10% obtenida por spray dried. Esto con el fin de tener alternativas de formulaciones. Both in the solubility index test and in the water and moisture absorption index tests, in addition to the selected formulation (Inu 15% obtained by lyophilization), 15% Inu formulations obtained by spray dried, MD 15% were evaluated. obtained by spray dried and Inu / MD (1: 2) 10% obtained by spray dried. This in order to have alternative formulations.
Para determinar el índice de solubilidad en agua se pesó 1 g de polvo en un matraz Erlenmeyer de 250 mL que contiene 100 mL de agua destilada. Se agito hasta disolver toda la muestra, luego se centrifugo a 3000 rpm durante 10 min. Se tomó una muestra representativa de 25 mL del sobrenadante y se pasó a placas de Petri. Finalmente, se secó la muestra en una estufa a 105°C por 5 h. La solubilidad (%) fue calculada por diferencia de peso. El índice de solubilidad del polvo estuvo en el rango de 88,9% y 97,0% (tabla 8), es decir, corresponde al porcentaje de sólidos que finalmente se disolvieron en el agua. Estos valores son bastante satisfactorios, ya que aseguran la disolución de la mayor parte de los componentes de la formulación. To determine the solubility index in water, 1 g of powder was weighed in a 250 mL Erlenmeyer flask containing 100 mL of distilled water. It was stirred until the whole sample was dissolved, then centrifuged at 3000 rpm for 10 min. A representative sample of 25 mL of the supernatant was taken and passed to Petri dishes. Finally, the sample was dried in an oven at 105 ° C for 5 h. Solubility (%) was calculated by weight difference. The solubility index of the powder was in the range of 88.9% and 97.0% (Table 8), that is, it corresponds to the percentage of solids that finally dissolved in the water. These values are quite satisfactory, since they ensure the dissolution of most of the components of the formulation.
Tabla 8. Solubilidad (%) del polvo seco obtenido a partir de zumo de limón (n=3).  Table 8. Solubility (%) of the dry powder obtained from lemon juice (n = 3).
Muestra g polvo/ 100 mL agua  Sample g powder / 100 mL water
Limón 5 Liofilizado Inu 15% 88,9  Lemon 5 Lyophilized Inu 15% 88,9
Limón 4 Liofilizado Inu 15% 87,5  Lemon 4 Lyophilized Inu 15% 87.5
Limón 5 Spray Dried Inu 15% 89.7  Lemon 5 Spray Dried Inu 15% 89.7
Limón 5 Spray Dried MD 15% 97,0  Lemon 5 Spray Dried MD 15% 97.0
Limón 5 Spray Dried Inu/MD (1:2) 10% 95.8  Lemon 5 Spray Dried Inu / MD (1: 2) 10% 95.8
Limón 4 Spray Dried Inu 15% 91,3  Lemon 4 Spray Dried Inu 15% 91.3
Limón 4 Spray Dried Inu/MD (1:2) 10% 95,7  Lemon 4 Spray Dried Inu / MD (1: 2) 10% 95.7
Limón 4 Spray Dried MD 15% No fue posible cuantiflcar  Lemon 4 Spray Dried MD 15% It was not possible to quantify
El ensayo del índice de absorción de agua permite evaluar el grado de higroscopicidad del polvo seco. Para ello se colocó 1 g del producto seco en placas de Petri a 25°C en un desecador que contiene una solución saturada de NaCI (75,4% de humedad relativa), después de 1 semana se pesaron las muestras. Los resultados se expresan como g de humedad por 100 g de sólidos secos (g /100 g). The water absorption index test allows to evaluate the degree of hygroscopicity of the dry powder. To this end, 1 g of the dried product was placed in Petri dishes at 25 ° C in a desiccator containing a saturated solution of NaCl (75.4% humidity). relative), after 1 week the samples were weighed. The results are expressed as g of moisture per 100 g of dry solids (g / 100 g).
En el caso de los polvos obtenidos a partir de zumos de limón, tenemos componentes altamente higroscópicos. Los resultados obtenidos (tabla 9) muestran valores entre 15,49 a 25,55 g/100 g de polvo seco, que son relativamente bajos, confirmando la eficiencia de los excipientes ayudantes de secado en la disminución de la higroscopicidad del polvo.  In the case of powders obtained from lemon juice, we have highly hygroscopic components. The results obtained (table 9) show values between 15.49 to 25.55 g / 100 g of dry powder, which are relatively low, confirming the efficiency of the drying auxiliary excipients in the reduction of the hygroscopicity of the powder.
Tabla 9. índice de absorción de agua del polvo seco obtenido a partir de zumo de limón (n=3). agua absorbida  Table 9. water absorption index of the dry powder obtained from lemon juice (n = 3). absorbed water
Muestra  Sample
g /100 g polvo  g / 100 g powder
Limón 5 Liofilizado Inu 15% 21,64 Lemon 5 Lyophilized Inu 15% 21.64
Limón 5 Liofilizado MD 15% 15,23Lemon 5 Lyophilized MD 15% 15,23
Limón 5 Liofilizado Inu/MD (1:2) 15% 16,18 Lemon 5 Lyophilized Inu / MD (1: 2) 15% 16,18
Limón 4 Liofilizado Inu 15% 21,6  Lemon 4 Lyophilized Inu 15% 21.6
Limón 4 Liofilizado MD 15% 15,49 Lemon 4 Lyophilized MD 15% 15.49
Limón 4 Liofilizado Inu/MD (1:2) 15% 19.98 Lemon 4 Lyophilized Inu / MD (1: 2) 15% 19.98
Limón 5 Spray Dryer Inu 15% 25,55 Limón 5 Spray Dryer MD 15% 22,44 Limón 5 Spray Dryer Inu/MD (1:2) 15% 22,41  Lemon 5 Spray Dryer Inu 15% 25,55 Lemon 5 Spray Dryer MD 15% 22,44 Lemon 5 Spray Dryer Inu / MD (1: 2) 15% 22,41
Limón 4 Spray Dryer Inu 15% 25,35 Limón 4 Spray Dryer Inu/MD (1:2) 15% 22.99  Lemon 4 Spray Dryer Inu 15% 25,35 Lemon 4 Spray Dryer Inu / MD (1: 2) 15% 22.99
EJEMPLO 2: Confección de la formulación. EXAMPLE 2: Preparation of the formulation.
Se diseñaron dos fórmulas con el fin de dilucidar el principio activo más importante en el mecanismo de acción antihipertensivo. Población 4 (mayor concentración en ácido ascórbico), población 5 (mayor concentración en flavonoides totales).  Two formulas were designed in order to elucidate the most important active principle in the mechanism of antihypertensive action. Population 4 (highest concentration in ascorbic acid), population 5 (highest concentration in total flavonoids).
El fitofármaco tendrá la siguiente composición, presentación, y forma de uso. FÓRMULA 1 (población 4) The phytodrug will have the following composition, presentation, and form of use. FORMULA 1 (population 4)
- Zumo desecado de frutos de C limón.. 2,044g g (1,64 mg EAA)*  - Desiccated juice of lemon C fruits .. 2.044g g (1.64 mg EAA) *
- Inulina . 3,204 g  - Inulin. 3,204 g
Presentación. Sachets de 5,24 gramos equivalentes a 9 mg de ácido ascórbico para su reconstitución en agua.  Presentation. Sachets of 5.24 grams equivalent to 9 mg of ascorbic acid for reconstitution in water.
FÓRMULA 2 (población 5)  FORMULA 2 (population 5)
- Zumo desecado de frutos de C limón.. 1,261 g (45,32 mg EQ)* - Desiccated juice of lemon C fruits .. 1,261 g (45.32 mg EQ) *
- Inulina . 2,070 g  - Inulin. 2,070 g
Presentación. Sachets de 3,39 gramos equivalentes a 14 mg equivalentes de quercetina para su reconstitución en agua.  Presentation. Sachets of 3.39 grams equivalent to 14 mg equivalents of quercetin for reconstitution in water.
La cantidad de cada componente del fitofármaco será determinada según los siguientes criterios:  The amount of each phytopharmaceutical component will be determined according to the following criteria:
Zumo desecado de frutos de C. Limón·, cantidad que otorgue al uso de un sachet la dosificación equivalente a la concentración de los marcadores químicos en el zumo de limón de un fruto corriente.  Desiccated fruit juice of C. Limón ·, amount that gives the use of a sachet the dosage equivalent to the concentration of chemical markers in the lemon juice of a common fruit.
Inulina: cantidad necesaria para otorgar a la formulación dispersabilidad y humectabilidad y efectos complementarios sobre la absorción de lípidos y azúcares. Inulin: amount necessary to give the formulation dispersibility and wettability and complementary effects on the absorption of lipids and sugars.
El fitofármaco será estandarizado en los marcadores químicos determinados para el zumo desecado y según la metodología desarrollada en el punto III.-. The phytodrug will be standardized in the chemical markers determined for the dried juice and according to the methodology developed in point III.-.
Como C limón es un fruto, está sometido a que sus principios activos cambien, en concentración, según la estación del año en que son cosechados, debido a esto se establece un rango de concentraciones de quercetina, que representa a los flavonoides totales presentes en zumo de limón. El rango determinado en este estudio es: 0,5 - 50 mg de equivalente de quercetina. Lo mismo ocurre con el ácido ascórbico. El rango es: 0,076 - 10 mg de equivalente de ácido ascórbico.  As C lemon is a fruit, it is subject to its active principles change, in concentration, according to the season of the year in which they are harvested, due to this a range of quercetin concentrations is established, which represents the total flavonoids present in juice of lemon. The range determined in this study is: 0.5 - 50 mg of quercetin equivalent. The same goes for ascorbic acid. The range is: 0.076 - 10 mg of ascorbic acid equivalent.
Estas concentraciones, han sido efectivas en el tratamiento de crisis hipertensivas, empíricamente.  These concentrations have been effective in the treatment of hypertensive crises, empirically.
Los gramos de inulina, deben ser recalculados según las concentraciones de los marcadores químicos. La relación con las otras poblaciones de C. limón, se mantienen en las diferentes estaciones. Entonces, la población 4 siempre será la más importante en contenido de ácido ascórbico y la población 5 la más importante con respecto al contenido de flavonoides totales. The grams of inulin must be recalculated according to the concentrations of the chemical markers. The relationship with the other C. lemon populations is maintained in the different seasons. Then, population 4 will always be the most important in ascorbic acid content and population 5 the most important with respect to the total flavonoid content.
Proceso de obtención de la formulación:  Process of obtaining the formulation:
- Masar 15 g de inulina y disponer en un vaso de precipitado de 200 mL.  - Mash 15 g of inulin and place in a 200 mL beaker.
- Llevar a 100 mL con zumo de limón.  - Take to 100 mL with lemon juice.
- Agitar con un agitador magnético hasta lograr una mezcla homogénea.  - Stir with a magnetic stirrer until a homogeneous mixture is obtained.
- Llevar a un balón de 500 mL y congelar rotando en baño de etanol.  - Take a 500 mL balloon and freeze rotating in an ethanol bath.
- Liofilizar y almacenar polvo obtenido a -20°C para evitar que capte humedad.  - Lyophilize and store powder obtained at -20 ° C to prevent it from picking up moisture.
EJEMPLO 3: Caracterización de la formulación. EXAMPLE 3: Characterization of the formulation.
Para caracterizar la liberación de los agentes activos desde polvo de zumo de C limón, se realizó un estudio de liberación in vitro, donde se cuantificó por espectrofotometría la concentración de un marcador químico representativo (equivalentes de quercetina y ácido ascórbico), utilizando una cantidad de polvo seco correspondiente al contenido de los sachets. El estudio se realizó en un equipo de disolución (Dissolution tester USP de Electrolab®), con paleta en 900 mL de medio gástrico simulado sin enzima, concentración de ácido clorhídrico 0,1N; temperatura 37°C, velocidad de giro de la paleta 100 RPM. Se tomaron muestras por duplicado con reposición de medio, cada quince minutos, fueron filtradas y diluidas se leyeron en espectrofotómetro a l= 280 nm (tabla 11).  To characterize the release of the active agents from lemon C lemon juice, an in vitro release study was carried out, where the concentration of a representative chemical marker (equivalents of quercetin and ascorbic acid) was quantified by spectrophotometry, using a quantity of dry powder corresponding to the content of the sachets. The study was carried out in a dissolution unit (Dissolution tester USP of Electrolab®), with a palette in 900 mL of simulated gastric medium without enzyme, concentration of 0.1 N hydrochloric acid; temperature 37 ° C, speed of rotation of the pallet 100 RPM. Samples were taken in duplicate with replenishment of medium, every fifteen minutes, they were filtered and diluted and read in spectrophotometer at l = 280 nm (table 11).
Tabla 11: Liberación de los agentes activos desde polvo de zumo de C. limón.  Table 11: Release of active agents from C. lemon juice powder.
Muestra Replica g polvo añadido a eq quercetina (mg) Sample Replica g powder added to eq quercetin (mg)
500mL de HCI 0,1N  500mL of HCI 0.1N
Población 4 1 9,671 22,6118  Population 4 1 9,671 22,6118
Población 4 2 10,3612 24,2255  Population 4 2 10.3612 24.2255
Población 5 1 5,1013 16,4325  Population 5 1 5,1013 16,4325
Población 5 2 4,8701 15,6878  Population 5 2 4.8701 15.6878
En el estudio de liberación in vitro se analizó la cantidad de quercetina disuelta en el tiempo. Para las poblaciones 4 y 5 se disolvieron 96,8 ± 4,5% y 94,8 ± 7,3% de quercetina, respectivamente, después de 15 minutos de ensayo. Estos resultados indican que los componentes activos del polvo de zumo de limón se disuelven muy rápidamente en el medio de disolución, quedando disponibles para su absorción, favoreciendo de esta manera su biodisponibilidad. In the in vitro release study, the amount of quercetin dissolved in time was analyzed. For populations 4 and 5, 96.8 ± 4.5% and 94.8 ± 7.3% of quercetin were dissolved, respectively, after 15 minutes of testing. This results they indicate that the active components of the lemon juice powder dissolve very quickly in the dissolution medium, being available for their absorption, thus favoring their bioavailability.
1. Estudios de estabilidad del fitofármaco  1. Phytopharmaceutical stability studies
Se realizó un estudio de estabilidad acelerada de los productos en su envase final, a una temperatura de 40°C ± 2°C y humedad relativa de 75% ± 5% en cámara climática y en condiciones normales, según normas de la Conferencia Internacional en Armonización (ICH). Se controlará la potencia del producto (estabilidad química) y características físicas; para el caso de la estabilidad química se empleará un método analítico indicador de estabilidad. Se debe evaluar la concentración de los marcadores químicos a 0, 30, 60 días para determinar si se encuentra dentro de los límites aceptables Se considerará como "cambio significativo" del producto: un cambio de un 10% de la concentración ¡nidal de principio activo; cualquier producto de degradación que se encuentre en cantidades fuera de su criterio de aceptación; y cambios en los criterios de aceptación del producto, como atributos físicos (apariencia).  An accelerated stability study of the products was carried out in its final packaging, at a temperature of 40 ° C ± 2 ° C and relative humidity of 75% ± 5% in the climatic chamber and under normal conditions, according to the International Conference Harmonization (ICH). The power of the product (chemical stability) and physical characteristics will be controlled; for the case of chemical stability, an analytical method of stability indicator will be used. The concentration of the chemical markers at 0, 30, 60 days must be evaluated to determine if it is within acceptable limits. A "significant change" of the product will be considered: a change of 10% of the nominal concentration of active principle. ; any degradation product that is in quantities beyond its acceptance criteria; and changes in product acceptance criteria, such as physical attributes (appearance).
A continuación se presentan las concentraciones de los respectivos marcadores químicos en las formulaciones sometidas a estudio de estabilidad en condiciones normales a tiempo 0, 30 y 60 días. Below are the concentrations of the respective chemical markers in the formulations submitted to stability study under normal conditions at time 0, 30 and 60 days.
No fue posible medir las concentraciones de los marcadores químicos en las formulaciones sometidas a condiciones aceleradas, debido a que la temperatura y humedad relativa perjudicaron las características físico organolépticas de las formulaciones. Por lo que fueron descartadas.  It was not possible to measure the concentrations of the chemical markers in the formulations subjected to accelerated conditions, because the temperature and relative humidity impaired the physical and organoleptic characteristics of the formulations. For what they were discarded.
Tabla 11. Concentraciones de ácido ascórbico a tiempo 0, 30 y 60 días (Form. 1).  Table 11. Concentrations of ascorbic acid at time 0, 30 and 60 days (Form 1).
Contenido ContenidoContent Content
Área Concentración Concentration Area
Lectura ác.ascórbico (pg)/ g ác.ascórbico (mg)/  Acid reading (pg) / g ac.ascorbic (mg) /
(mV.s) (pg/mL)  (mV.s) (pg / mL)
polvo_ sachet  powder_ sachet
Tiempo 0  Time 0
1 3675,036 180,291 1776,269 9,3151 3675,036 180,291 1776,269 9,315
2 3695,773 181,223 1785,447 9,3632 3695,773 181,223 1785,447 9,363
3 3673,902 180,240 1775,768 9,3123 3673,902 180,240 1775,768 9,312
4 3662,073 179,709 1770,533 9,285 4 3662,073 179,709 1770,533 9,285
mg  mg
9,319 ác.ascórbico/sachet Tiempo 30 9,319 asccorbic / sachet Time 30
1 7760,686 159,285 1548,408 8,120 1 7760,686 159,285 1548,408 8,120
2 7445,853 152,792 1485,296 7,7892 7445,853 152,792 1,485,296 7,789
3 8369,478 171,839 1670,448 8,7603 8369,478 171,839 1670,448 8,760
4 7503,791 153,987 1496,911 7,850 4 7503,791 153,987 1,496,911 7,850
mg  mg
8,130 ác.ascórbico/sachet  8,130 ascorbic / sachet
Tiempo 60  Time 60
1 3506,836 172,736 1717,056 9,004 1 3506,836 172,736 1717,056 9,004
2 3692,542 181,078 1799,977 9,4392 3692,542 181,078 1799,977 9,439
3 3758,435 184,038 1829,400 9,5933 3758,435 184,038 1829,400 9,593
4 3687,039 180,831 1797,520 9,426 4 3687,039 180,831 1797,520 9,426
mg  mg
9,366 ác.ascórbico/sachet  9,366 acc.ascorbic / sachet
Las concentraciones de ácido ascórbico y las características físico organolépticas y tecnológicas de la Formulación 1 se mantuvieron estables durante el período de estudio. The concentrations of ascorbic acid and the physical, organoleptic and technological characteristics of Formulation 1 remained stable during the study period.
5 Tabla 12. Concentraciones de flavonoides totales expresados en equivalentes de quercetina a tiempo 0, 30 y 60 días. 5 Table 12. Concentrations of total flavonoids expressed in quercetin equivalents at time 0, 30 and 60 days.
Concentración Concentración ConcentraciónConcentration Concentration Concentration
Abs quercetina quercetina quercetina Abs quercetin quercetin quercetin
(mg/mL) (mg)/ g polvo (mg)/sachet (mg / mL) (mg) / g powder (mg) / sachet
Tiempo 0 Time 0
1 0,5355 0,0332 3,3078 11,213 1 0.5355 0.0332 3.3078 11.213
2 0,5315 0,0329 3,2831 11,1302 0.5315 0.0329 3.2831 11.130
3 0,506 0,0314 3,1256 10,5963 0.506 0.0314 3.1256 10.596
4 0,5129 0,0318 3,1682 10,740 4 0.5129 0.0318 3.1682 10.740
Concentración  Concentration
quercetina (mg)/sachet 10,920 promedio  quercetin (mg) / sachet 10,920 average
Tiempo 30 _  Time 30 _
1 0,6735 0,0417 4,1429 14,044 1 0.6735 0.0417 4.1429 14,044
2 0,6022 0,0373 3,7043 12,5582 0.6022 0.0373 3.7043 12.558
3 0,5904 0,0366 3,6317 12,3123 0.5904 0.0366 3.6317 12.312
4 0,5825 0,0361 3,5831 12,147 4 0.5825 0.0361 3.5831 12.147
Concentración  Concentration
quercetina (mg)/sachet 12,765 promedio  quercetin (mg) / sachet 12,765 average
Tiempo 60  Time 60
1 0,6722 0,0417 4,1814 14,175 1 0.6722 0.0417 4.1814 14.175
2 0,6641 0,0412 4,1310 14,0042 0.6641 0.0412 4.1310 14.004
3 0,6778 0,0420 4,2162 14,293 0,6542 0,0406 4,0694 13,795 3 0.6778 0.0420 4.2162 14.293 0.6542 0.0406 4.0694 13,795
Concentración  Concentration
quercetina (mg)/sachet 14,067
Figure imgf000022_0001
quercetin (mg) / sachet 14,067
Figure imgf000022_0001
Las concentraciones de quercetina aumentaron en un 28% durante el período de estudio. Esto puede tener explicación en las características del método de cuantificación (formación de complejos), el que puede estar captando azúcares y grupos fenólicos de éstos. Las características físico organolépticas y tecnológicas de la Formulación 2 se mantuvieron estables. Quercetin concentrations increased by 28% during the study period. This may be explained by the characteristics of the quantification method (complex formation), which may be picking up sugars and phenolic groups of these. The physical-organoleptic and technological characteristics of Formulation 2 remained stable.
EJEMPLO 4: ESTUDIO DE LA EFICACIA DE LA FORMULACION. EXAMPLE 4: STUDY OF THE EFFECTIVENESS OF THE FORMULATION.
El fitofármaco se reconstituye en agua de tal forma que permita la dosificación equivalente a la concentración de los marcadores químicos en el zumo de limón de un fruto corriente. The phytopharmaceutical is reconstituted in water in such a way that allows the dosage equivalent to the concentration of the chemical markers in the lemon juice of a common fruit.
Se realizó un estudio piloto con la participación de 15 personas hipertensas en tratamiento medicamentoso, que poseen un esfigmomanómetro y que aceptaron a someterse a esta prueba en su casa. Cada paciente acepto las condiciones del estudio a través de un consentimiento informado. A pilot study was conducted with the participation of 15 hypertensive people in drug treatment, who have a sphygmomanometer and who agreed to undergo this test at home. Each patient accepted the study conditions through an informed consent.
El protocolo que cada paciente tuvo que realizar fue el siguiente: The protocol that each patient had to perform was the following:
- tomar la presión arterial en reposo todos los días, - take resting blood pressure every day,
- si tiene una presión arterial con valores ¡guales o mayores a 140/90 mmHg (alza de presión) consumir el fitofármaco según indicaciones - if you have a blood pressure with values equal to or greater than 140/90 mmHg (boost in pressure) consume the phytodrug as directed
- registrar la presión arterial a los 10, 15, 20, 30 y 60 minutos. - record blood pressure at 10, 15, 20, 30 and 60 minutes.
Se llevará a cabo por un período de 1 mes, como mínimo, para cada paciente. It will be carried out for a period of at least 1 month for each patient.
Reporte de caso con crisis de hipertensión. Case report with hypertension crisis.
De las 15 personas que participaron solo una hizo crisis durante en el estudio.  Of the 15 people who participated, only one made a crisis during the study.
Paciente mujer de 25 años de edad, con diagnóstico de hipertensión arterial desde hace tres años. La paciente no presenta otras enfermedades de base. En relación a la hipertensión, la paciente mantiene presiones diarias de 150/90 mmHg. La paciente sufre de frecuentes crisis hipertensivas. Patient, a 25-year-old woman with a diagnosis of high blood pressure for three years. The patient does not have other underlying diseases. In relation to hypertension, the patient maintains daily pressures of 150/90 mmHg. The patient suffers from frequent hypertensive crises.
Durante el período de estudio la paciente sufrió cinco crisis hipertensivas y fue sometida a las 2 formulaciones.  During the study period, the patient suffered five hypertensive crises and underwent the 2 formulations.
Los sachets eran disueltos en un vaso de agua y se administraban en el momento en que se detectaba la crisis hipertensiva. La presión se controló a los 0, 5, 10, 15, 30 y 60 minutos de administrado el preparado, obteniéndose los siguientes resultados: The sachets were dissolved in a glass of water and administered at the time the hypertensive crisis was detected. The pressure was controlled at 0, 5, 10, 15, 30 and 60 minutes after the preparation was administered, obtaining the following results:
Formulación 2 Formulation 2
Al analizar las presiones arteriales sistólicas y diastólicas individualmente se obtienen los resultados mostrados en las figuras 1 y 2 respectivamente. Se observa una clara disminución de ambas presiones a los cinco minutos de administrada la formulación 2.By analyzing the systolic and diastolic arterial pressures individually, the results shown in figures 1 and 2 respectively are obtained. A clear decrease of both pressures was observed five minutes after the formulation 2 was administered.
Tabla 13. Registro de las presiones arteriales obtenidas durante dos crisis hipertensivas luego de la administración del sachet con la formulación 2. Table 13. Registry of arterial pressures obtained during two hypertensive crises after administration of the sachet with formulation 2.
Minutos luego Minutes later
de Presión arterial Presión arterial  of Blood Pressure Blood Pressure
administración (sist/diást mmHg) (sist/diást mmHg) del fitofármaco  administration (sist / diast mmHg) (sist / diast mmHg) of the phytodrug
0 159/101 156/111 0 159/101 156/111
5 145/93 139/93 5 145/93 139/93
10 138/91 139/84 10 138/91 139/84
15 136/91 148/8615 136/91 148/86
30 137/86 134/9430 137/86 134/94
60 134/86 128/78 60 134/86 128/78
En relación a la presión sistólica se observa una disminución de 14 mmHg a los 5 minutos de la primera crisis y de 17 mmHg en la segunda, disminuyendo un promedio de 15,5 mmHg. A los 10 minutos se observa en ambos casos una disminución de la presión arterial sistólica a valores de presión arterial normal alta, que en general tienden a disminuir aún más a medida que pasan los minutos, manteniéndose los niveles de presión arterial hasta la hora. En relación a la presión arterial diastólica, la disminución de la presión arterial es diferente en ambas crisis, siendo mucho mayor en la segunda crisis, sin embargo en ambos casos se obtuvo niveles de presión cercanos a una presión arterial normal alta a los 5 minutos, la que continúa disminuyendo a medida que va pasando el tiempo. In relation to systolic pressure, a decrease of 14 mmHg was observed at 5 minutes after the first seizure and 17 mmHg in the second, decreasing an average of 15.5 mmHg. At 10 minutes in both cases a decrease in systolic blood pressure is observed at high normal blood pressure values, which tend to decrease even more as the minutes pass, maintaining blood pressure levels until the hour. In relation to diastolic blood pressure, the decrease in blood pressure is different in both crises, being much higher in the second crisis, however in both cases pressure levels were obtained close to a normal high blood pressure at 5 minutes, which continues to decrease as time goes by.
Formulación 1  Formulation 1
Tabla 14. Registro de las presiones arteriales obtenidas durante dos crisis hipertensivas luego de la administración del sachet con la formulación 1.  Table 14. Record of arterial pressures obtained during two hypertensive crises after administration of the sachet with formulation 1.
Minutos luego de Minutes after
administración del Presión arterial Presión arterial Presión arterial fitofármaco (sist/diástmm Hg) (sist/diástmm Hg) (sist/diástmm Hg) administration of blood pressure blood pressure phytopharmaceutical blood pressure (sist / diastmm Hg) (sist / diastmm Hg) (sist / diastmm Hg)
0 154/96 161/98 149/92 0 154/96 161/98 149/92
5 144/96 146/93 137/83 5 144/96 146/93 137/83
10 142/86 143/92 130/80 10 142/86 143/92 130/80
15 137/85 143/87 132/7815 137/85 143/87 132/78
30 135/85 131/83 132/7830 135/85 131/83 132/78
60 134/77 132/83 131/79 60 134/77 132/83 131/79
En relación a la presión arterial sistólica, se observa una reducción en promedio de 12 mmHg a los 5 minutos de administrado el limón. La reducción en la presión arterial sistólica es un poco menor que para el caso de la formulación 2, sin embargo, el efecto obtenido permite alcanzar niveles cercanos a una presión arterial normal alta a los 10 minutos y continúa bajando a lo largo de los minutos (figura 3). In relation to systolic blood pressure, an average reduction of 12 mmHg was observed 5 minutes after the lemon was administered. The reduction in systolic blood pressure is slightly lower than in the case of formulation 2, however, the effect obtained allows reaching levels close to a normal high blood pressure at 10 minutes and continues to decrease over the minutes ( figure 3).
El efecto en la presión arterial diastólica no es homogéneo en las distintas crisis, encontrándose niveles cercanos a lo normal a los 10 minutos en la mayoría de los casos y normal a los 15 minutos. Al igual que en las mediciones anteriores el efecto se mantiene en el tiempo (figura 4).  The effect on diastolic blood pressure is not homogeneous in the different crises, with levels close to normal at 10 minutes in most cases and normal at 15 minutes. As in the previous measurements, the effect is maintained over time (figure 4).
Al comparar las presiones arteriales medias (PAM) en ambas poblaciones se observa que a pesar que los valores de presión se encontraban muy elevados, a los 5 minutos se alcanzan valores de PAM dentro de lo normal. En la formulación 1 este efecto se alcanza en general a los 10 minutos. En ambos casos los valores se obtienen dentro de lo normal hasta la hora de control (figuras 5 y 6).  When comparing the mean arterial pressures (MAP) in both populations, it is observed that even though the pressure values were very high, within 5 minutes PAM values were reached within normal limits. In the formulation 1 this effect is reached in general at 10 minutes. In both cases the values are obtained within normal until the control time (figures 5 and 6).

Claims

REIVINDICACIONES
1. Una formulación fitoterapéutica en polvo para la reconstitución en agua u otra base acuosa, CARACTERIZADA porque comprende: 1. A herbal phytotherapeutic formulation for reconstitution in water or another aqueous base, CHARACTERIZED because it comprises:
a. 1,0 - 2,5 g de zumo desecado de frutos de C. limón, y  to. 1.0 - 2.5 g of dried fruit juice of C. lemon, and
b. 2,0 - 3,5 g de polisacárido.  b. 2.0 - 3.5 g of polysaccharide.
2. Una formulación fitoterapéutica en polvo, según reivindicación 1, CARACTERIZADA porque la cantidad de zumo desecado de frutos de C. limón comprende 0,5 - 50 mg de equivalente de quercetina y/o 0,076 - 10 mg de equivalente de ácido ascórbico. 2. A powdered phytotherapeutic formulation, according to claim 1, characterized in that the quantity of dried fruit juice of C. lemon comprises 0.5-50 mg of quercetin equivalent and / or 0.076-10 mg of ascorbic acid equivalent.
3. Una formulación fitoterapéutica en polvo, según reivindicación 1, CARACTERIZADA porque el polisacárido se puede seleccionar desde inulina, maltodextrina, dextrosa, fibras solubles o fibras dietarías. 3. A powder phytotherapeutic formulation, according to claim 1, CHARACTERIZED because the polysaccharide can be selected from inulin, maltodextrin, dextrose, soluble fibers or dietary fibers.
4. Una formulación fitoterapéutica en polvo, según reivindicación 1, CARACTERIZADA porque el polisacárido le otorga dispersabilidad y humectabilidad al producto. 4. A powder phytotherapeutic formulation, according to claim 1, characterized in that the polysaccharide gives dispersibility and wettability to the product.
5. Uso de la formulación fitoterapéutica en polvo, según reivindicación 1, CARACTERIZADA porque su utilización permite una disminución de hasta 10 mmHg en pacientes con alzas de presión, sin ejercer efectos hipotensivos ya que no disminuye la presión arterial en pacientes normotensos. 5. Use of the phytotherapeutic powder formulation, according to claim 1, CHARACTERIZED because its use allows a decrease of up to 10 mmHg in patients with pressure increases, without exerting hypotensive effects since blood pressure does not decrease in normotensive patients.
6. Uso de la formulación fitoterapéutica en polvo para la reconstitución en agua, según reivindicación 1, CARACTERIZADA porque sirve para preparar un medicamento útil en caso de crisis hipertensiva. 6. Use of the phytotherapeutic powder formulation for reconstitution in water, according to claim 1, characterized in that it serves to prepare a useful medicine in case of hypertensive crisis.
7. Uso de la formulación fitoterapéutica en polvo, según reivindicación 1, CARACTERIZADA porque sirve para preparar un medicamento útil como complemento a las terapias de manejo de alzas de presión arterial. 7. Use of the herbal phytotherapeutic formulation, according to claim 1, characterized in that it serves to prepare a useful medicine as a complement to the therapies for managing blood pressure increases.
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