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    • 专利摘要:
    Pre-filled injectable device for the treatment of cerebral edema in acute mountain sickness. The authors of the present invention have developed a pre-filled injectable device comprising or consisting of the composition of the invention, the injectable pharmaceutical form, the combined preparation, or the pre-filled injectable device for the treatment of cerebral edema in acute mountain sickness. The properties of this device make it useful for administration under extreme environmental conditions and when urgent treatment is required. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2663669A1
    申请号:ES201631190
    申请日:2016-09-13
    公开日:2018-04-16
    发明作者:Antonio HUETE ALLUT；Francisco Dámaso FERNÁNDEZ GINÉS；Francisco SIERRA GARCÍA；Sergio GARCÍA MUÑOZ；Ignacio Manuel RODRÍGUEZ GARCÍA；Juan Miguel EXPÓSITO LÓPEZ；María José PEULA PORTALES
    申请人:Servicio Andaluz de Salud；Universidad de Almeria；
    IPC主号:
    专利说明:

    Preloaded injectable device for the treatment of cerebral edema
    FIELD OF THE INVENTION
    The present invention is within the field of medicine and pharmacy, and refers
    5 to the use of a composition comprising a corticosteroid, a gastric acid suppressing agent, and at least one Group B Vitamin, preferably contained in a pre-filled injectable device, for the treatment of cerebral edema, preferably due to acute mountain sickness.
    10 BACKGROUND OF THE INVENTION
    Acute mountain sickness (MAM), colloquially called altitude sickness, wasteland, soroche, aiming or puna, is the organism's lack of adaptation to hypoxia (lack of oxygen) of altitude. The severity of the disorder is directly related to the speed of ascent and the altitude reached. Conversely, these symptoms usually disappear at
    15 descend to lower levels. It normally occurs from 2,400 meters of altitude, to the so-called "death zone" at 8,000 meters of altitude.
    It usually appears from exposure to hypoxia and is more frequent in children under fifty years of age and in subjects who usually reside less than 900 meters.
    The main cause of this affliction is hypoxia (lack of oxygen in the body). The pressure
    Atmospheric temperature decreases with height, which affects the bioavailability of oxygen, since the pulmonary alveoli are not capable of transporting the same amount of oxygen to the blood as in a situation of higher pressure. Although it is known that hypoxia is the cause of MAM, the exact mechanism by which it causes it is still unknown.
    The amount of oxygen available to support mental and psychological attention decreases
    25 according to the altitude. The availability of oxygen and nitrogen, as well as its density, decrease as the altitude increases. Also, dehydration due to an accelerated loss of water in the form of steam due to altitude can contribute to the symptoms of altitude sickness. The speed with which one ascends, the initial height, the physical activity, as well as the individual susceptibility are factors that contribute to this malaise. Altitude sickness can be prevented by ascending slowly. In most cases, the symptoms are temporary and usually reduce as acclimatization to altitude occurs. Without
    However, in extreme cases, altitude sickness can be fatal.
    The symptoms will also depend on the rate of ascent and the effort that is made, and can range from mild to life-threatening and can affect the nervous system, lungs, muscles and heart.
    The symptoms of mild to moderate acute mountain sickness may include: difficulty sleeping,
    10 dizziness or feeling of vertigo, fatigue, headache, lack of appetite, nausea or vomiting, rapid heart rate, and difficulty breathing with effort.
    Symptoms in the most severe cases include: cyanosis, stiffness or chest congestion, confusion, cough, blood expectoration, decreased state of consciousness or isolation from social interaction, pale or grayish complexion, inability to walk in a straight line or
    15 absolute inability to walk, and respiratory distress at rest.
    Early diagnosis is important, since acute mountain sickness is easier to treat in the early stages. The main treatment for all forms of mountain sickness is to descend or descend to a lower altitude as fast and safe as possible, you should not continue ascending if symptoms occur. One of the first-line treatments is to administer an extra oxygen supply. For the treatment of mild symptoms and pulmonary edema, the diuretic acetazolamide (Diamox) is usually administered. If the individual has pulmonary edema, treatment may include: oxygen, an antihypertensive (nifedipine), beta-agonist inhalers, phosphodiesterase (sildenafil) inhibitor, and dexamethasone (Decadron) to help reduce cerebral edema. Likewise, hyperbaric chambers
    25 laptops allow mountaineers to simulate conditions at lower altitudes without actually moving from the place on the mountain. These devices are very useful in case the bad weather or other factors make it impossible to descend the mountain.
    Even so, complications such as coma, pulmonary edema, cerebral edema may occur, which can lead to seizures, mental disorders or permanent damage to the nervous system, including death. People with severe mountain sickness may need hospitalization, and it is necessary to develop compositions for adequate treatment for immediate administration in emergencies, and that are stable in the long term and in extreme environmental conditions.
    5 BRIEF DESCRIPTION OF THE INVENTION
    A first aspect of the invention relates to a composition, hereinafter composition of the invention, comprising one or more corticosteroids, one or more gastric acid suppressing agents, and at least one Vitamin of group B or any of its ester salts, tautomers, solvates and hydrates, or any combination thereof. In a preferred embodiment the
    The composition of the invention consists of a corticosteroid, a gastric acid suppressing agent, and at least one Vitamin of group B or any of its ester salts, tautomers, solvates and hydrates, or any combination thereof.
    In a preferred embodiment, the corticosteroid is selected from the list consisting of Betamethasone, Dexamethasone, Methylprednisolone, Parametasone, Prednisolone, Prednisone, Triamcinolone, Hydrocortisone, Deflazacort, Fludrocortisone, or any combination thereof. In an even more preferred embodiment, the corticosteroid is Dexamethasone. More preferably, Dexamethasone is in a concentration of between 0.5 and 100 milligrams per 15 ml of the total volume of the preparation (plv). Even more preferably, Dexamethasone is in a concentration of 40 milligrams per 15 ml of the total volume of the
    20 prepared (p / v).
    In another preferred embodiment of the first aspect of the invention, the gastric acid suppressing agent is selected from the list consisting of Misoprostol, Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole, Ranitidine, Cimetidine, Famotidine, Nizatidine, Roxatidine, Roxatidine of zinc and Guaiazulene or any of its combinations.
    In an even more preferred embodiment, the gastric acid suppressing agent is Ranitidine. More preferably, Ranitidine is in a concentration of between 5 and 100 milligrams per 15 ml of the total volume of the preparation (w / v). Even more preferably, Ranitidine is in a concentration of 50 milligrams per 15 ml of the total volume of the preparation (plv).
    In another preferred embodiment, the Vitamin S group is selected from the list consisting of Thiamine, Pyridoxine Hydrochloride, and Cyanocobalamin or any combination thereof. In an even more preferred embodiment, Thiamine (Vitamin S1) is in a concentration of between 10 and 250 milligrams per 15 ml of the total volume of preparation 5 (w / v). More preferably, Thiamine (Vitamin S1) is in a concentration of 100 milligrams per 15 ml of the total volume of the preparation (w / v). In another even more preferred embodiment, the Pyridoxine Hydrochloride (Vitamin B6) is in a concentration of between 30 and 500 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, the Pyridoxine Hydrochloride (Vitamin B6) is in a concentration of 300 milligrams per 15 ml of the total volume of the preparation (plv). In another even more preferred embodiment, Cyanocobalamin (Vitamin 812) is in a concentration of between 0.5 and 5 milligrams per 15 ml of the total volume of the preparation (w / v). Preferably, Cyanocobalamin (Vitamin S12) is in a concentration of between 1 and 2 milligrams per 15 ml of the total volume of the preparation (plv). Plus
    15 preferably, Cyanocobalamin (Vitamin 812) is in a concentration of 2 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, Cyanocobalamin (Vitamin S1 2) is in a concentration of 1 milligram per 15 ml of the total volume of the preparation (plv).
    Preferably, the composition comprises as the only active ingredients a corticosteroid, a gastric acid suppressing agent, and Vitamins of the S group, although it may comprise pharmaceutically acceptable excipients and / or vehicles.
    In another preferred embodiment of the first aspect of the invention, the composition is a pharmaceutical composition.
    In another preferred embodiment, the composition is contained in an opaque container.
    In another preferred embodiment of the first aspect of the invention, the composition further comprises another active ingredient. In an even more preferred embodiment, the other active ingredient is selected from the list consisting of antacids, antiflatulents. antinauseous, prokinetic, diuretic, analgesic, antimiginous, local anesthetics, antiepileptic, and antioxidant vitamins or any combination thereof.
    In another preferred embodiment, the composition further comprises pharmaceutically acceptable excipients. In a more preferred embodiment, pharmaceutically acceptable excipients are selected from the list consisting of: 1M Sodium Hydroxide (E-524), Sodium Chloride, Sodium Citrate (E-331i), Creatinine, Disodium Edetate, Glycerol
    5 (E-422), Sodium Hydrogen Phosphate Dihydrate, Sodium Hydrogen Carbonate, Phenol, Sodium Metabisulfite and water for injection, or any combination thereof. In an even more preferred embodiment, the composition comprises additional pharmaceutically acceptable excipients.
    In another more preferred embodiment the composition of the invention comprises excipients.
    10 pharmaceutically stable under extreme environmental conditions of pressure and temperature. In an even more preferred embodiment, the excipients are pharmaceutically stable at atmospheric pressure between 2000 and 100,000 meters high. In another even more preferred embodiment, the excipients are pharmaceutically stable at an ambient temperature between -50 and 50 ° C (degrees Celsius).
    A second aspect of the invention relates to an injectable pharmaceutical form, hereinafter injectable pharmaceutical form of the invention, comprising the composition of the invention. In a preferred embodiment, the injectable pharmaceutical form of the invention is selected from a sterile solution, suspension, or emulsion.
    In a preferred embodiment of this second aspect of the invention, the administration form is selected from intramuscular (1M), intravenous (IV), or subcutaneous (Se). In a more preferred embodiment, the administration form is intramuscular (1M).
    A third aspect of the invention relates to a combined preparation, hereinafter combined preparation of the invention, comprising:
    a) A component A: one or more corticosteroids as described in the first aspect of the invention.
    b) A component B: one or more gastric acid suppressing agents as described in the first aspect of the invention.
    c) A component C: at least one vitamin of group B as described in the first aspect of the invention
    or any of its salts esters, tautomers, solvates and hydrates, or any combination thereof.
    In a preferred embodiment, it refers to the combined preparation of the invention consisting of:
    a) A component A: one or more corticosteroids as described in the first aspect of the invention.
    b) A component B: one or more gastric acid suppressing agents as described in the first aspect of the invention.
    c) A component C: at least one vitamin of group B as described in the first aspect of the invention
    or any of its salts esters, tautomers, solvates and hydrates, or any combination thereof.
    In another preferred embodiment, the corticosteroid is selected from the list consisting of Betamethasone, Dexamethasone, Methylprednisolone, Parametasone, Prednisolone, Prednisone, Triamcinolone, Hydrocortisone, Deflazacort, Fludrocortisone, or any combination thereof. In an even more preferred embodiment, the corticosteroid is Dexamethasone. More preferably, Dexamethasone is in a concentration of between 0.5 and 100 milligrams per 15
    20 ml of the total volume of the preparation (w / v). Even more preferably, Dexamethasone is in a concentration of 40 milligrams per 15 ml of the total volume of the preparation (w / v).
    In another preferred embodiment of the first aspect of the invention, the acid suppressing agentgastric is selected from the list consisting of Misoprostol, Omeprazole, Pantoprazole,25 Lansoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole, Ranitidine, Cimetidine, Famotidine,Nizatidine, Roxatidine, Zinc Acexamate and Guaiazulene or any combination thereof.In an even more preferred embodiment, the gastric acid suppressing agent is Ranitidine. Pluspreferably, Ranitidine is in a concentration of between 5 and 100 milligrams
    for every 15 ml of the total volume of the preparation (w / v). Even more preferably, Ranitidine is in a concentration of 50 milligrams per 15 ml of the total volume of the preparation (plv).
    In another preferred embodiment, the Group 8 Vitamin is selected from the list consisting of
    5 Thiamine, Pyridoxine Hydrochloride, and Cyanocobalamin or any combination thereof. In an even more preferred embodiment, Thiamine (Vitamin 81) is in a concentration of between 10 and 250 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, Thiamine (Vitamin 81) is in a concentration of 100 milligrams per 15 ml of the total volume of the preparation (plv).
    In another even more preferred embodiment, the Pyridoxine Hydrochloride (Vitamin B6) is in a concentration of between 30 and 500 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, the Pyridoxine Hydrochloride (Vitamin B6) is in a concentration of 300 milligrams per 15 ml of the total volume of the preparation (plv). In another even more preferred embodiment, cyanocobalamin (Vitamin 812) is in a
    15 concentration between 0.5 and 5 milligrams per 15 ml of the total volume of the preparation (w / v). Preferably, Cyanocobalamin (Vitamin 812) is in a concentration of between 1 and 2 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, Cyanocobalamin (Vitamin 812) is in a concentration of 2 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, the
    20 Cyanocobalamin (Vitamin 812) is in a concentration of 1 milligram for every 15 ml of the total volume of the preparation (w / v).
    In another preferred embodiment of this aspect of the invention, the combined preparation further comprises another active ingredient that is selected from the list consisting of antacids, anti-flatulent, anti-nauseous, prokinetic, diuretic, analgesic, anti-migraine,
    25 local anesthetics, antiepileptics, and antioxidant vitamins or any combination thereof.
    In another preferred embodiment, the combined preparation further comprises pharmaceutically acceptable excipients and / or vehicles.
    A fourth aspect of the invention relates to a pre-filled injectable device comprising the composition, the injectable pharmaceutical form or the combined preparation of the invention or any combination thereof.
    In a preferred embodiment of this aspect of the invention, the administration bottle is selected from intramuscular (1M), intravenous (IV), or subcutaneous (SC). In a more preferred embodiment, the administration form is intramuscular (1M).
    In another preferred embodiment of this aspect of the invention, the pre-filled injectable device comprises a plastic body, a cartridge, a needle, a plunger, and a controlled release mechanism or any combination thereof. In one embodiment
    10 more preferred, the plastic body is flexible. In another more preferred embodiment, the plastic body is made of polyethylene. In another more preferred embodiment, the needle is covered by a protective cap. In another more preferred embodiment, the controlled release mechanism is activated by a metering button.
    A fifth aspect of the invention relates to the use of the composition, the pharmaceutical form.
    Injectable, the combined preparation or the pre-filled injectable device of the invention in the preparation of a medicament for the prevention, improvement, relief and / or treatment of cerebral edema. Alternatively, the present aspect of the invention relates to the composition, the injectable pharmaceutical form, the combined preparation or the pre-filled injectable device of the invention for use in the prevention, improvement, relief and / or treatment of cerebral edema.
    20 In a preferred embodiment, cerebral edema is caused by hypoxia, trauma, hypertension, ischemia, spontaneously in genetically predisposed individuals or any combination thereof.
    In another preferred embodiment, cerebral edema is caused by hypoxia. In an even more preferred embodiment, hypoxia is due to exposure to great heights.
    In another preferred embodiment, cerebral edema is due to acute mountain sickness.
    In another preferred embodiment, administration is performed intramuscularly (1M), intravenously (IV), or subcutaneously (SC). In a more preferred embodiment, administration is performed intramuscularly (1M).
    In another preferred embodiment, administration is performed at a single dose or emergency dose. In a more preferred embodiment, administration is performed when the patient has clinical symptoms.
    BRIEF DESCRIPTION OF THE FIGURES
    5 Figure 1. Spectrum 'H-NMR of the Ranitidine standard.
    Figure 2. 'H-NMR spectrum of the Dexamethasone pattern.
    Figure 3. 'H-NMR spectrum of the thiamine pattern. The signals corresponding to the excipients phenol and glycerol are indicated.
    Figure 4. 'H-NMR spectrum of the pyridoxine pattern. The signals corresponding to the phenol excipient are indicated.
    Figure 5. 'H-NMR spectrum of the cyanocobalamin pattern.
    Figure 6. H-NMR spectrum of the mixture of the invention at initial time.
    Figure 7. Signal comparison of the 'H-NMR spectra of the individual standard compounds with the mixture of the invention at initial time. The conservation of
    15 the signals of the initial compounds.
    Figure 8. Enlargement of a region of the 'H-NMR spectrum of the individual standard compounds with the mixing of the invention at initial time.
    Figure 9. Comparison of the 'H-NMR spectra of the mixture at initial time and after 28 days at freezing temperature. The preservation of the signals of the initial mixture 20 can be checked.
    Figure 10. Comparison of the 'H-NMR spectra of the mixture at initial time and after 28 days at cooling temperature. The preservation of the signals of the initial mixture can be checked.
    Detailed description of the invention
    The authors of the present invention have developed a composition, preferably contained in a pre-filled injectable device, which has great stability under extreme high altitude environmental conditions, for the treatment of cerebral edema in the disease.
    5 sharp mountain.
    The symptomatic characteristics of MAM are the symptoms and signs of encephalopathy, including ataxic gait, severe lassitude, and progressive deterioration of mental function, speech and consciousness disorders (irritability, confusion, drowsiness, stupor, and coma among others) . The therapeutic arsenal currently available comprises a series of agents for the symptomatic treatment of oral administration. This route of administration is the one of choice under normal conditions, but it presents a series of difficulties in the case of high altitude conditions, among which it stands out from a poor tolerance to the tablet due to the difficulty in swallowing, until the time it takes in absorbing and presenting a systemic effect. Although some of the agents described are available for
    15 Intramuscular administration, a new drawback is presented, since the patient would have to reconstitute the vial and self-administer it, taking into account the extreme environmental conditions, which can affect the physicochemical stability of the preparation, together with the patient's pathological state. .
    The present invention provides solutions to the technical problems described and as a whole the
    20 data provided suggest that the active substances contained in the injectable device are structurally stable at extreme weather conditions for at least 28 days, time necessary for any planned expedition. Likewise, the bioavailability of the active substances is improved, reducing the absorption time at the systemic level and therefore accelerating the therapeutic effect. Thus the present invention presents greater ease of
    25 administration, intramuscularly, combining in a single device all the active substances necessary for the immediate management of the acute states of the disease.
    COMPOSITION OF THE INVENTION
    Therefore, a first aspect of the invention relates to a composition, hereinafter composition of the invention, comprising one or more corticosteroids, one or more gastric acid suppressing agents, and at least one Vitamin B group or any of its you go out
    5 esters, tautomers, solvates and hydrates, or any combination thereof. In a preferred embodiment the composition of the invention consists of a corticosteroid, a gastric acid suppressing agent, and at least one Group B Vitamin or any of its ester, tautomeric, solvate and hydrate salts, or any combination thereof.
    In a preferred embodiment, the corticosteroid is selected from the list consisting of
    10 Betamethasone, Dexamethasone, Methylprednisolone, Parametasone, Prednisolone, Prednisone, Triamcinolone, Hydrocortisone, Deflazacort, Fludrocortisone, or any combination thereof. In an even more preferred embodiment, the corticosteroid is Dexamethasone. More preferably, Dexamethasone is in a concentration of between 0.5 and 100 milligrams per 15 ml of the total volume of the preparation (w / v). Even more preferably, Dexamethasone is
    15 found in a concentration of 40 milligrams per 15 ml of the total volume of the preparation (w / v).
    In another preferred embodiment of the first aspect of the invention, the gastric acid suppressing agent is selected from the list consisting of Misoprostol, Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole, Ranitidine, Cimetidine, Famotidine, Nizatidine, Roxatidine, Roxatidine Zinc acexamate and Guaiazulene or any combination thereof. In an even more preferred embodiment, the gastric acid suppressing agent is Ranitidine. More preferably, Ranitidine is in a concentration of between 5 and 100 milligrams per 15 ml of the total volume of the preparation (plv). Even more preferably, Ranitidine is in a concentration of 50 milligrams per 15 ml of the total volume of
    25 prepared (plv).
    In another preferred embodiment, Vitamin B group is selected from the list consisting of Thiamine, Pyridoxine Hydrochloride, and Cyanocobalamin or any combination thereof. In an even more preferred embodiment, Thiamine (Vitamin B1) is in a concentration of between 10 and 250 milligrams per 15 ml of the total volume of preparation 30 (w / v). More preferably, Thiamine (Vitamin B1) is in a concentration of 100

    milligrams per 15 ml of the total volume of the preparation (plv). In another even more preferred embodiment, the Pyridoxine Hydrochloride (Vitamin B6) is in a concentration of between 30 and 500 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, the Pyridoxine Hydrochloride (Vitamin B6) is in a concentration of 300 milligrams per 15 ml of the total volume of the preparation (w / v). In another even more preferred embodiment, Cyanocobalamin (Vitamin B12) is in a concentration of between 0.5 and 5 milligrams per 15 ml of the total volume of the preparation (w / v). Preferably, cyanocobalamin (Vitamin B12) is in a concentration of between 1 and 2 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, Cyanocobalamin (Vitamin B12) is in a concentration of 2 milligrams per 15 ml of the total volume of the preparation (plv). More preferably, Cyanocobalamin (Vitamin B12) is in a concentration of 1 milligram per 15 ml of the total volume of the preparation (w / v). Preferably, the composition comprises as sole active ingredients a corticosteroid, a gastric acid suppressing agent , and Group B vitamins, although it may comprise pharmaceutically acceptable excipients and / or vehicles.
    In another preferred embodiment of the first aspect of the invention, the composition is a pharmaceutical composition.
    In another preferred embodiment, the composition is contained in an opaque container. In a more preferred embodiment, the packages containing the composition in the liquid state are selected from syringes, ampoules or vials, and carpule, or any combination thereof. In an even more preferred embodiment, the packages containing the composition in liquid state are topaz color.
    In another preferred embodiment of the first aspect of the invention, the composition further comprises another active ingredient. In an even more preferred embodiment, the other active ingredient is selected from the list consisting of antacids, anti-flatulent, anti-nauseous, prokinetic, diuretic, analgesic, anti-migraine, local anesthetics, anti-epileptic, and antioxidant vitamins or any combination thereof.
    More preferably, the diuretic of choice is Acetazolamide. More preferably, the analgesic is selected from non-steroidal anti-inflammatory drugs (Al NE) and compounds derived from salicylic acid. Even more preferably, the NSAID is ibuprofen. Even more preferably, the salicylic acid derivative is aspirin. More preferably, the antimiginous of choice is Sumatriptan. More preferably, the antiepileptic is Gabapentin.
    In another preferred embodiment, the composition further comprises pharmaceutically acceptable excipients. Such excipients can be selected from those known in the state of the art.
    In a more preferred embodiment, pharmaceutically acceptable excipients are selected from the list consisting of: 1M Sodium Hydroxide (E-524), Sodium Chloride, Sodium Citrate (E331i), Creatinine, Disodium Edetate, Glycerol (E -422), Sodium Hydrogen Phosphate Dihydrate,
    10 Sodium hydrogen carbonate, Fenal, Sodium metabisulfite and water for injection, or any combination thereof. In an even more preferred embodiment, the composition comprises additional pharmaceutically acceptable excipients.
    In another more preferred embodiment the composition of the invention comprises pharmaceutically stable excipients under extreme ambient conditions of pressure and temperature. In
    In an even more preferred embodiment, the excipients are pharmaceutically stable at atmospheric pressure between 2000 and 100,000 meters high. In another even more preferred embodiment, the excipients are pharmaceutically stable at an ambient temperature between -50 and 50 ° C (degrees Celsius).
    As for pharmaceutically stable excipients in extreme environmental conditions
    20 of pressure and temperature as defined herein make reference to those excipients known in the state of the art that provide physicochemical characteristics that allow maintaining the stability of the composition of the invention at high altitude conditions. An example of cryoprotective excipients could be, but not limited to, those that are selected from:
    25 Cryoprotectants of low molecular and permeable weights; methanol, propylene glycol, ethylene glycol, dimethylsulfoxide, 2,3 butanediol, glycerol, and other alcohols.
    Low molecular weight and non-permeable cryoprotectants; galactose, glucose, sucrose, trehalose and other carbohydrates or carbohydrates.
    High molecular weight and non-permeable cryoprotectants, among which polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronidate and other polymers stand out.
    The term "active ingredient", "drug", "active substance", "pharmaceutically active substance", "active ingredient" or "pharmaceutically active ingredient" as used herein means any component that potentially provides an activity pharmacological or other different effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or that affects the structure or function of the body of man or other animals. The term includes those components that promote a chemical change in
    10 the preparation of the drug and are present therein in a modified form provided that provides the specific activity or effect.
    The term "corticosteroid" or "corticosteroid" as defined herein refers to a variety of honnones of the steroid group, produced by the cortex of the adrenal glands, and their derivatives, which are involved in a variety of
    15 physiological mechanisms, including those that regulate inflammation, the immune system, carbohydrate metabolism, protein catabolism, plasma electrolyte levels and, finally, those that characterize the stress response. These substances can be synthesized artificially and have therapeutic applications, being used mainly due to their anti-inflammatory and immunosuppressive properties and their effects on metabolism.
    20 When "gastric acid suppressing agents" is mentioned herein, it refers to all those active ingredients whose main action is based on reducing the production of acid in gastric juice, through various mechanisms of action, such as prostaglandin agonists, H2 receptor antagonists, or proton pump inhibitors, and which are mainly used for the treatment of peptic ulcer and reflux
    25 gastroesophageal
    When the "Group B Vitamins" is mentioned herein, it refers to a set of eight water-soluble vitamins related to cellular metabolism and nerve impulse conduction, among which we find: Vitamin B1 (aunt mine), Vitamin B2 (riboflavin), Vitamin B3 (niacin), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine), Vitamin B8 (biotin, also known as vitamin H), Vitamin B9 (folic acid), and Vitamin B12 (cyanocobalamin).
    The term "antacid" as described in the present invention is a substance, generally a base (alkaline medium), which acts against the acids generated by the
    5 parietal glands, alkalizing the stomach increasing the pH. A selection of antacids can be sodium bicarbonate (NaHC03), calcium carbonate (CaC03) and magnesium hydroxide (Mg (OH) 2) or aluminum.
    The term "antiflatulent" refers to those agents that act on the distention of the digestive system caused by an excessive accumulation of gases.
    10 The term "prokinetic" refers to those agents that are used to improve intestinal transit, improving emptying speed and sphincter function.
    The term "diuretic" as used herein refers to those drugs that cause the elimination of water and electrolytes in the body through urine.
    15 The term "analgesics" as used herein refers to those drugs that soothe or eliminate pain.
    The term "antimigrañosos" refers to the therapeutic group administered in cases of migraine or migraine.
    The term "local anesthetics" refers to those drugs that decrease the sensitivity 20 at the administration site, temporarily and perceptibly preventing the conduction of the electrical impulse by the membranes of the localized nerves and muscle.
    The "antiepileptic" therapeutic group, also called anticonvulsants, refers to those drugs intended to combat, prevent or interrupt seizures or seizures.
    25 The term "antioxidant vitamins" refers to essential nutrients that act as catalysts for physiological processes (directly and indirectly) and also prevent molecular oxidation.

    The term "therapeutically effective amount" refers to the amount of the agent or
    compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, by the characteristics of the compounds, in addition to age, patient's condition, severity of the alteration or disorder, and of the route and frequency of administration.
    Here, when reference is made to the term "salts, esters, tautomers, solvates and hydrates" refers to any pharmaceutically acceptable salt, ester, tautomer, solvate or hydrate, or any other compound that, in its administration, is capable of provide (directly or indirectly) a compound such as those described herein. However, it will be noted that pharmaceutically unacceptable salts also fall within the scope of the invention, since these may be useful for the preparation of pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the state of the art.
    The term "solvate ~, as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compounds present in the composition of the invention that can be used in the manufacture of a medicament, such as pharmaceutically unacceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts.The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable.In a particular embodiment, the solvate is a hydrate.The solvates can be obtained by conventional methods of solvation known to those skilled in the art.
    The pharmaceutical composition as mentioned in the invention can be administered topically, transdermally, orally, nasally, intramuscularly, intravenously, intraperitoneally, subcutaneously, enterally or parenterally. Illustrative examples of topical or transdermal administration include, but are not limited to, iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections, needleless injections by pressure, microelectric patches and any combination thereof. Illustrative examples of oral administration pharmaceutical sources include tablets, capsules, granules, solutions, suspensions, etc., and may contain conventional excipients, such as binders, diluents, disintegrants, lubricants, humectants, etc., and may be prepared. by conventional methods. The pharmaceutical compositions can also be adapted for parenteral administration, in the form of, for example, sterile lyophilized solutions, suspensions or products, in the appropriate dosage form; in this case, said pharmaceutical compositions will include suitable excipients, such as
    5 buffers, surfactants, etc. In any case, the excipients will be chosen based on the pharmaceutical form of administration selected. A review of the different pharmaceutical forms of drug administration and their preparation can be found in the book "Treaty of Galenic Pharmacy", by C. Fauli i Trillo, 10 Edition, 1993, Luzán 5, S.A. of Editions.
    The pharmaceutically acceptable adjuvants and vehicles that can be used in said compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.
    According to the EMEA definition, any component in the composition other than an active substance is considered excipient. An example of additional excipients
    Pharmaceutically acceptable could be, but not limited to, those that are selected from the list consisting of: methanol, propylene glycol, ethylene glycol, dimethyl sulfoxide, 2,3 butanediol, glycerol, and other alcohols, galactose, glucose , sucrose, trehalose and other carbohydrates or carbohydrates, polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronidate and other polymers, or any combination thereof.
    20 INJECTABLE PHARMACEUTICAL FORM OF THE INVENTION
    A second aspect of the invention relates to an injectable pharmaceutical form, hereinafter injectable pharmaceutical form of the invention, comprising the composition of the invention. In a preferred embodiment, the injectable pharmaceutical form of the invention is selected from a sterile solution, suspension, or emulsion.
    In a preferred embodiment of this second aspect of the invention, the administration form of the injectable pharmaceutical form of the invention is selected from intramuscular (1M), intravenous (IV), or subcutaneous (SC). In a more preferred embodiment, the administration form is intramuscular (1M).
    In another preferred embodiment the injectable fan-pharmaceutical form of the invention comprises pharmaceutically stable excipients. Examples of excipients that can be used in the injectable pharmaceutical form of the invention include, but are not limited to: antimicrobial preservatives, such as methylparaben, propylparaben; antioxidants, such as
    5 sodium metabisulfite, propyl gallate; stabilizing and suspending agents, such as soluble or swellable modified celluloses, for example sodium carboxymethyl cellulose (Aquasorb, Blanose, Nymcel); tonicity agents, such as sodium chloride; or solubilizers, such as propylene glycol or polyethylene glycols. These excipients must be within the limits of the definition of the invention.
    10 In this report, "pharmaceutical source" means the mixture of one or more active ingredients with or without additives that have physical characteristics for proper dosage, preservation, administration and bioavailability.
    In another preferred embodiment of the present invention, the pharmaceutical form comprising the composition of the invention is injectable. More preferably, the pharmaceutical source
    Injectable of the invention is selected from sterile solution, suspension, or emulsion. Other fan-pharmaceutical forms may be, but are not limited to, colloidal systems, which include nanoemulsions, nanocapsules and polymeric nanoparticles, among others. Compositions for injectable or parenteral administration can be prepared by conventional methods of Galenic Pharmacy, as mixing and dispersion.
    The term "solution" or "solution" is defined as a homogeneous mixture consisting of a solvent and one or more solutes.
    The term "suspension" refers to a heterogeneous mixture formed by a solid or by small non-soluble particles (dispersed phase) that are dispersed in a liquid medium (dispersing or dispersing phase).
    The term "emulsion" refers to a mixture of two immiscible liquids in a more or less homogeneous manner.
    The term "intramuscular injection" is a form of rapid administration in which the medication is injected into the muscle.
    The term "intravenous injection" is a form of administration even faster than the intramuscular in which the drug is injected into the venous system, so that the active ingredients immediately reach the systemic circulation of the patient.
    The term "subcutaneous injection" is a form of administration in which the medication is injected into the subcutaneous tissue.
    COMBINED PREPARATION OF THE INVENTION
    A third aspect of the invention relates to a combined preparation, hereinafter combined preparation of the invention, comprising:
    a) A component A: one or more corticosteroids as described in the first aspect of the invention.
    b) A component B: one or more gastric acid suppressing agents as described in the first aspect of the invention.
    c) A component C: at least one vitamin of group B as described in the first aspect of the invention
    15 or any of its salts esters, tautomers, solvates and hydrates, or any combination thereof.
    In a preferred embodiment, it refers to the combined preparation of the invention consisting of:
    a) A component A: one or more corticosteroids as described in the first aspect of the invention.
    b) A component B: one or more gastric acid suppressing agents as described in the first aspect of the invention.
    c) A component C: at least one vitamin of group 8 as described in the first aspect of the invention
    or any of its salts esters, tautomers, solvates and hydrates, or any combination thereof.
    In another preferred embodiment, the corticosteroid is selected from the list consisting of 8etamethasone, Dexamethasone, Methylprednisolone, Parametasone, Prednisolone, Prednisone, Triamcinolone, Hydrocortisone, Deflazacort, Fludrocortisone, or any combination thereof. In an even more preferred embodiment, the corticosteroid is Dexamethasone. More preferably, Dexamethasone is in a concentration of between 0.5 and 100 milligrams per 15 ml of the total volume of the preparation (w / v). Even more preferably, Dexamethasone is in a concentration of 40 milligrams per 15 ml of the total volume of the
    10 prepared (p / v).
    In another preferred embodiment of the first aspect of the invention, the gastric acid suppressing agent is selected from the list consisting of Misoprostol, Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole, Ranitidine, Cimetidine, Famotidine, Nizatidine, Roxatidine, Roxatidine of zinc and Guaiazulene or any of its combinations.
    In an even more preferred embodiment, the gastric acid suppressing agent is Ranitidine. More preferably, Ranitidine is in a concentration of between 5 and 100 milligrams per 15 ml of the total volume of the preparation (w / v). Even more preferably, Ranitidine is in a concentration of 50 milligrams per 15 ml of the total volume of the preparation (w / v).
    In another preferred embodiment, the Group 8 Vitamin is selected from the list consisting of Thiamine, Pyridoxine Hydrochloride, and Cyanocobalamin or any combination thereof. In an even more preferred embodiment, Thiamine (Vitamin 81) is in a concentration of between 10 and 250 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, Thiamine (Vitamin 81) is in a concentration of 100
    25 milligrams per 15 ml of the total volume of the preparation (plv). In another even more preferred embodiment, the Pyridoxine Hydrochloride (Vitamin 86) is in a concentration of between 30 and 500 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, the Pyridoxine Hydrochloride (Vitamin 86) is in a concentration of 300 milligrams per 15 ml of the total volume of the preparation (w / v).
    In another even more preferred embodiment, Cyanocobalamin (Vitamin 812) is in a
    S 10 concentration of between 0.5 and 5 milligrams per 15 ml of the total volume of the preparation (w / v). Preferably, cyanocobalamin (Vitamin 812) is in a concentration of between 1 and 2 milligrams per 15 ml of the total volume of the preparation (plv). More preferably, Cyanocobalamin (Vitamin 812) is in a concentration of 2 milligrams per 15 ml of the total volume of the preparation (w / v). More preferably, Cyanocobalamin (Vitamin 812) is in a concentration of 1 milligram per 15 ml of the total volume of the preparation (plv). In another preferred embodiment of this aspect of the invention, the combined preparation of the invention further comprises another active ingredient that is selected from the list consisting of antacids, antiflatulent, anti-nauseous, prokinetic, diuretic, analgesic, antimiginous, local anesthetics, antiepileptic, and antioxidant vitamins or any combination thereof.
    fifteen More preferably, the diuretic of choice is Acetazolamide. More preferably, the analgesic is selected from non-steroidal anti-inflammatory drugs (Al NE) and compounds derived from salicylic acid. Even more preferably, the NSAID is ibuprofen. Even more preferably, the salicylic acid derivative is aspirin. More preferably, the antimiginous of choice is Sumatriptan. More preferably, the antiepileptic is Gabapentin.
    In another preferred embodiment, the combined preparation further comprises pharmaceutically acceptable excipients and / or vehicles.
    20 25 It should be emphasized that the term "combined preparation" or also called "juxtaposition", herein, means that the components of the combined preparation need not be present as a joint, for example in a composition, in order to be available for separate application or sequential. In this way, the expression "juxtaposed" implies that it is not necessarily a true combination, in view of the physical separation of the components.
    PRECARGED INJECTABLE DEVICE OF THE INVENTION
    A fourth aspect of the invention relates to a pre-filled injectable device comprising the composition, the injectable fan-pharmaceutical form or the combined preparation of the invention or any combination thereof.
    In a preferred embodiment of this aspect of the invention, the method of administration is selected from intramuscular (1M), intravenous (IV), or subcutaneous (Se). In a more preferred embodiment, the administration form is intramuscular (1M).
    In another preferred embodiment of this aspect of the invention, the pre-filled injectable device 5 of the invention comprises a plastic body, a cartridge, a needle, a plunger, and a controlled release mechanism or any combination thereof. In a more preferred embodiment, the plastic body is flexible. In another more preferred embodiment, the plastic body is made of polyethylene. In another more preferred embodiment, the needle is covered by a protective cap. In another more preferred embodiment, the controlled release mechanism is activated by a metering button.
    In another more preferred embodiment, a pre-filled injectable device may be single dose or multidose. Preferably the pre-filled injectable device is single dose.
    "Pre-filled injectable device" means any syringe, pen, dispenser or pump pre-filled with single-use, active substances or principles of small size, which is activated by pressing the plunger, administering the active substance at a constant rate Through a needle. As described in the invention, the device is formed by a needle, a needle guard, and a pre-filled syringe, pen, dispenser or pump which contains the composition, the injectable pharmaceutical form or the combined preparation of the invention arranged for immediate administration without the need to assemble and load the
    20 injectable or the presence of specialized health personnel, so that it is suitable for emergencies in high mountains.
    USE OF THE COMPOSITION, THE INJECTABLE PHARMACEUTICAL FORM, THE COMBINED PREPARATION OR THE PRE-CHARGED INJECTABLE DEVICE OF THE INVENTION
    A fifth aspect of the invention relates to the use of the composition, the injectable pharmaceutical form, the combined preparation or the pre-filled injectable device of the invention in the preparation of a medicament for the prevention, improvement, relief and / or treatment of edema. cerebral. Alternatively, the present aspect of the invention relates to the composition, the
    injectable pharmaceutical form, the combined preparation or the pre-filled injectable device of the invention for use in the prevention, improvement, relief and treatment of cerebral edema.
    In a preferred embodiment of this aspect of the invention, cerebral edema is caused by hypoxia, trauma, hypertension, ischemia, spontaneously in genetically predisposed individuals or any combination thereof.
    In another preferred embodiment, cerebral edema is caused by hypoxia. In an even more preferred embodiment, hypoxia is due to exposure to great heights.
    In another preferred embodiment, cerebral edema is due to acute mountain sickness.
    Another preferred embodiment of this fifth aspect of the invention relates to the prevention, improvement, relief and treatment of cerebral edema of acute mountain sickness.
    In another preferred embodiment, administration is performed intramuscularly (1M), intravenously (IV), or subcutaneously (Se). In a more preferred embodiment, administration is performed intramuscularly (1M).
    In another preferred embodiment, administration is performed at a single dose or dose of
    15 emergency. In a more preferred embodiment, administration is performed when the patient has clinical symptoms. The administration of additional doses will depend on the transfer time of the individual to a health center.
    The term "medicament", as used herein, refers to any substance used for prevention, diagnosis, relief, treatment or cure of diseases in man and animals.
    The term "treatment" as understood in the present invention refers to combating the effects caused as a result of a disease or pathological condition of interest in a subject (preferably mammal, and more preferably a human) that includes:
    (i) inhibit the disease or pathological condition, that is, stop its development;
    25 (ii) alleviate the disease or the pathological condition, that is, cause the regression of the disease or the pathological condition or its symptomatology;
    (iii) stabilize the disease or pathological condition.
    The term "prevention" as understood in the present invention is to prevent the onset of disease, that is, to prevent the occurrence of disease or the pathological condition in a subject (preferably mammal, and more preferably a human), in
    5 particularly when said subject has a predisposition for the pathological condition.
    The compositions of the present invention can be used together with other medicaments in combination therapies. The other drugs may be part of the same composition or of a different composition, for administration at the same time or at different times.
    Both the compositions of the present invention, as well as the combined preparation can be formulated for administration to an animal, and more preferably to a mammal, including man, in a variety of ways known in the state of the art. Such combined compositions or preparations and / or their formulations can be administered to an animal, including a mammal and, therefore, to man, in a variety of ways, including,
    15 but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intrathecal, intraventricular, oral, enteral, parenteral, intranasal or dermal.
    Administration of the compositions or pharmaceutical forms of the present invention can be accomplished by any suitable method, such as intramuscular, subcutaneous, or intravenous infusion. Intramuscular administration is preferred by the
    20 pharmacokinetic convenience and the severity of the disease to be treated.
    The amount of active ingredients present in the composition of the invention will depend on the relative efficacy of the compounds chosen, the severity of the disease to be treated and the weight of the patient. It is important to note that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as
    25 modifications in the route of administration.
    The term "cerebral edema" refers to an accumulation of fluid in the intra or extracellular spaces of the brain. Four types of Cerebral Edema are distinguished: Cytotoxic, with the passage of fluid from the extracellular to the intracellular space; Vasogenic, passage of the vascular torrent fluid to the extracellular; Interstitial, passage of cerebrospinal fluid (CSF) into the extracellular space (edema seen in hydrocephalus) and hyperemic, caused by an increase in intravascular volume. Cerebral edema caused by hypoxia occurs by local vasodilation of cerebral blood vessels that causes blood flow to the capillaries to increase and therefore pressure. This produces an outflow of fluid to the brain tissue. This
    5 results in characteristic symptoms, such as severe headache, progressive mental confusion and loss of consciousness.
    The term "hypoxia" as mentioned in the present invention refers to hypobaric hypoxia due to exposure to great heights and occurs when there is a decrease in atmospheric pressure, maintaining the same concentration of oxygen in the air (20.9% ). The pressure of 02 in the atmosphere is reduced by decreasing the atmospheric pressure, the difference in pressure between the alveoli and the venous blood of the pulmonary capillaries decreases and therefore so does the oxygen pressure in arterial blood, being diminished the contribution of oxygen to the cells. This type of hypoxia is what gives rise to acute mountain sickness, which results in cerebral edema between the second and third day of permanence in
    15 height.
    Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and
    20 drawings are provided by way of illustration, and are not intended to be limiting of the present invention.
    The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention.
    EXAMPLES OF THE INVENTION
    The invention will now be illustrated by means of Nuclear Magnetic Resonance (NMR) spectroscopic techniques performed by the inventors, which show the stability of the composition of the invention and the injectable pharmaceutical form of the invention.
    Nuclear Magnetic Resonance Spectroscopy is an ideal technique for this purpose since it allows the structural characterization of the compounds involved in the
    mixture, being able to determine the nature of eventual by-products of the interaction of the components. Specifically, in the present invention the Proton Nuclear Magnetic Resonance (l H.RMN) was used.
    S Example 1. Determination of the stability of the composition of the invention under extreme environmental conditions by means of 1 H-NMR
    10 In order to determine the stability of the composition of the invention, the patterns of the corresponding active ingredients of the composition on the one hand have been structurally characterized by means of H-NMR spectra (Figure 1-5), and the mixing of the composition of the invention by another, the latter at initial time (Figure 6) and after 28 days of preservation of the mixture at temperature ranges 2 ° C to 8 ° C; and frozen in a temperature range of -16 ° C to -30 ° C.
    lS It has been possible to verify the stability of the mixture based on the presence of signals, identical to those of the standard compounds, unaltered in the initial mixture under the aforementioned test conditions and subsequently after the time and storage temperatures analyzed.
    Materials and methods
    Active ingredients of the composition.
    The molecular structures and systematic names of the active ingredients that are part of the composition of the invention are detailed below:
    twenty Ranitidine 50mg / 5ml (formula 1): IUPAC Denomination: (E) -N- (2 - ((5 - ((dimethylaminomethyl) furan 2-yl) methylthio) ethyl) -N'-methyl-2-nitroethane-1, 1 -diamine.
    yH, n (.... N ~ .... ~ S ~ AH, C O N H NO .... CH3N H
    (one)
    Dexamethasone 40 mg / 15 mL (formula 11): IUPAC Denomination: Phosphate 9-fluoro-11j3, 17.21trihydroxy-16a-methylpregna-1, 4-diene-3,20-dione.
    OH
    OR
    (eleven)
    S Thiamine (vitamin B1) 100 mg / 15 mL (formula 111): IUPAC Denomination: 2- [3 - [(4-amino-2-methylpyrimidine-5-yl) methyl) -4-methyl-thiazol-5-yl) ethanol
    "'-, / N NH, S N "XlhN ~ ~ ~ OH
    (111)
    Pyridoxine Hydrochloride (vitamin B6) 300 mg / 15 mL (formula IV): IUPAC Denomination: 4,5-Bis (hydroxymethyl) -2-methylpyridin-3-o1.
    OH
    OH OH
    "N
    10 (IV) Cyanocobalamin (vitamin B12) 1000 ~ gl 15 mL. (Fonnula V): IUPAC Denomination:
    CobaIto (3+); [(2R, 3S, 4R, 5S) -5- (5, 6-dimethyl benzimidazol-1-yl) -4-h idroxy-2- (h id roxi methy) oxollan-3il] [(2R) -1 - [3 [(1 R, 2R, 3R, 5Z, 7S, 10Z, 12S, 13S, 15Z, 17S, 18S, 19R) -2, 13,18-tris (2-amino-2-oxoethyl)
    7,12,17 -tris (3-amino-3-oxopropyl} -3,5,8,8, 13, 15, 18, 19-octamethyl-2, 7,12, 17-tetrahydro-1 H-corrina24- id-3-yl) propanoylamino) propane-2-yl) phosphate; cyanide.
    (V)
    s Excipients of the composition.
    1M Sodium Hydroxide (E-524), Sodium Chloride, Sodium Citrate (E-331i), Creatinine, Disodium Edetate, Glycerol (E-422), Sodium Dihydrogen Phosphate Dihydrate, Sodium Hydrogen Carbonate, Phenol, Sodium Metabisulfite , and water for injection.
    Preparation of the mixture
    10 For the preparation of the mixture, work has been carried out inside the Horizontal Laminar Flow Cabin with sterile gloves, hat and mask to ensure sterility during the manufacturing process.
    lS The measurements of the 1H-NMR spectra were carried out at room temperature on a Bruker Advance DRX 600 MHZ® spectrometer equipped with a 5 mm single-axis z-gradient probe.
    29
    The preparation of the composition of the invention has been carried out at room temperature immediately before the spectroscopic determination. Once the measurement has been made (time O), it is stored refrigerated in a temperature range of 2 ° e to 8De; and frozen in a temperature range of -16De to -30De, making new 5 measures of them at 28 days.
    To carry out the characterizations by 'H-NMR, sterile polypropylene syringes, needles, NMR tube, and deuterated DMSO capillaries have been used, the latter in order to obtain the lock at deuterium frequency. Different experiments have been carried out, performing the spectroscopic determination of the patterns of
    10 the corresponding active ingredients and subsequently of the composition of the invention. To this end, the different substances are incorporated into an NMR tube with a deuterated DMSO capillary inside, at room temperature immediately before the spectroscopic determination. Results
    15 The spectral assignment of the signals obtained for each pattern is presented below. This assignment was taken as a reference when interpreting the spectra obtained from the composition of the invention under the different conditions tested: Ranitidine:
    'H NMR (600 MHz, DMSO-d6) 1i 6.76 (d, J = 1.1 Hz, 1 H), 6.56 (d, J = 3.4 Hz, 1H), 6.30 (s, 1 H),
    20 4.21 (s, 2H), 3.76 (s, 2H), 3.37 (1, J = 6.7 Hz, 2H), 2.83 (sa, 2H), 2.74 (s, 9H). Dexamethasone:
    'H NMR (600 MHz, DMSO- (6) O7.00 (d, J = 10.1 Hz, 1H), 5.88 (dd, J = 10.1, 2.0 Hz, 1H), 5.68 (s, 1H), 4.03 (dd , J = 19.0, 5.1 Hz, 1H), 3.90 -3.80 (m, 1H), 2.56 -2.44 (m, 1H), 2.24 -2.16 (m, 1H), 1.97 -1.88 (m, 1H), 1.65 (di , J = 13.8, 3.3 Hz, 1H), 1.56 (Id, J = 11 .9, 8.3 Hz, 1H), 1.41 (di,
    25 J = 11 .0, 4.7 Hz, 1H), 1.34 -1.19 (m, 1H), 1.12 (d, J = 14.2 Hz, 1H), 1.00 (s, 3H), 0.92 (qd, J = 13.2, 5.2 Hz, 1H), 0.71 (ddd, J = 12.3, 8.2.3.9 Hz, 1H), 0.45 (s, 3H), 0.35 (d, J = 7.3 Hz, 3H).
    Thiamine:
    'H NMR (600 MHz, DMSO- (6): O 9.57 (s, 1 H), 7.92 (s, 1 H), 5.47 (s, 2H), 3.80 (1, J = 5.8 Hz, 1 H), 3.10 (1, J = 5.8 Hz, 1H), 2.54 (s, 3H), 2.45 (s, 3H).
    Pyridoxine Hydrochloride:
    'H NMR (600 MHz, DMSO- (6): O 7.88 (s, 1H), 4.84 (s, 4H), 2.48 (s, 3H). 5 Cyanocobalamin:
    'H NMR (600 MHz, DMSO- (6): O 7.18 (s, 1H), 6.99 (s, 1H), 6.41 (s, 1H), 6.26 (d, J = 3.4 Hz, 1H),
    5.99 (s, 1 H), 4.24 -4.18 (m, 1 H), 4.18 (1, J = 3.7 Hz, 1 H), 4.09 (dd, J = 9.6, 1.6 Hz, 1H), 4.00 (d, J = 10.8 Hz, 1 H), 3.99 -3.93 (m, 1 H), 3.83 (dd, J = 13.0, 2.7 Hz, 1 H), 3.69 -3.61 (m, 1 H), 3.51 (d, J = 15.4 Hz, 1H), 3.33 (dd, J = 11.9, 5.6 Hz, 1 H), 3.26 (s, 1H), 3.27 -3.21 (m, 1H), 2.86 (dd, J
    10 = 14.7, 9.4 Hz, 1H), 2.66 (dd, J = 11.8.8.6 Hz, 1H), 2.62 -2.55 (m, 2H), 2.57 -2.50 (m, 3H), 2.49 (s, 1H), 2.48 (s, 3H), 2.47 (s, 1H), 2.46 (s, 1H), 2.45 (s, 3H), 2.41 (dd, J = 9.9, 7.0 Hz, 1H),
    2.33 (d, J = 13.5 Hz, 1H), 2.29 (d, J = 13.4 Hz, 1H), 2.17 (d, J = 2.0 Hz, 6H), 2.14 (s, 1H), 2.10 (d, J = 14.4 Hz, 1 H), 2.01 (d, J = 3.3 Hz, 1 H), 1.96 -1.85 (m, 5H), 1.82 (s, 1 H), 1.77 (s, 3H), 1.75 1.68 (m, 1H), 1.35 (s, 3H), 1.31 (s, 3H), 1.29 (s, 3H), 1.16 (d, J = 6.5 Hz, 3H), 1.10 (s, 3H), 0.98
    15 0.88 (m, 2H)
    When the signals of the 1 H-NMR spectra of the individual standard compounds are compared with the mixture of the invention at the initial time, the conselVation of the signals of the initial compounds can be seen (Figure 7-8). When the 1 H-NMR spectra of the mixture are compared at initial time and after 28 days at
    20 freezing temperature, the preservation of the signals of the initial mixture can be checked (Figure 9).
    When the 1 H-NMR spectra of the mixture are compared at the initial time and after 28 days at cooling temperature, the preservation of the signals of the initial mixture can be checked (Figure 10).
    25 The active ingredients of the composition generally showed stability under extreme conditions, although a low concentration of cyanocobalamin was identified in the mixture, so that due to this it would be necessary to overdose the mixture with 1 mg of vitamin
    812 additional pure, because the difference in concentrations between this component and the majority exceeds the dynamic range of the technique.
    5 Example 2. Preparation of the injectable pharmaceutical form of the invention
    The preparation of the injectable pharmaceutical form has been carried out under sterile conditions inside the horizontal laminar flow cabinet (CFL), with sterile gloves, hat and mask.
    First, 50 mg of Ranitidine, 40 mg of Dexamethasone, 100 mg are mixed in a syringe
    10 mg of Thiamine, 300 mg of Pyridoxine Hydrochloride, and 1000iJg of Cyanocobalamin, in addition to the excipients of the invention, in a final volume of 15ml.
    Next, a 0.22mJ sterilizing filter (previously saturated with water for injection -API-) has been placed to remove any interfering particles.
    Subsequently the mixture has been transferred through the filter to a 20 ml syringe with
    15 photoprotection, a protective cap has been placed on the needle of said syringe, and it has been packaged in sterile conditions.
    Finally, a visual control of the mixture has been carried out to check the cleanliness, and the absence of suspended particles.
    20 P2016311 90
    权利要求:
    Claims (45)
    [1]
    one. A composition comprising one or more corticosteroids, one or more gastric acid suppressing agents, and at least one Vitamin B group or any of its ester, tautomeric, solvate and hydrate salts, or any combination thereof.
    [2]
    2. The composition according to the preceding claim, wherein the corticosteroid is selected from the list consisting of Betamethasone, Dexamethasone, Methylprednisolone, Parametasone, Prednisolone, Prednisone, Triamcinolone, Hydrocortisone, Deflazacort, Fludrocortisone, or any combination thereof.
    [3]
    3. The composition according to any of claims 1-2, wherein the corticosteroid is Dexamethasone.
    [4]
    Four. The composition according to any of claims 1-3, wherein the Dexamethasone is in a concentration of between 0.5 and 100 milligrams per 15 ml of the total volume of the preparation (w / v).
    [5]
    5. The composition according to any of claims 1-4, wherein the Dexamethasone is in a concentration of 40 milligrams per 15 ml of the total volume of the preparation (plv).
    [6]
    6. The composition according to any of claims 1-5, wherein the gastric acid suppressing agent is selected from the list consisting of Misoprostol, Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole, Ranitidine, Cimetidine, Famotidine, Nizatidine, Roxatidine, Zinc acexamate and Guaiazulene or any combination thereof.
    [7]
    7. The composition according to any of claims 1-6, wherein the gastric acid suppressing agent is Ranitidine.
    [8]
    8. The composition according to any of claims 1-7, wherein Ranitidine is in a concentration of between 5 and 100 milligrams per 15 ml of the total volume of the preparation (w / v).
    [9]
    9. The composition according to any of claims 1-8, wherein the Ranitidine is in a concentration of 50 milligrams per 15 ml of the total volume of the preparation (plv).
    [10]
    10. The composition according to any of claims 1-9, wherein the Vitamin of the
    Group B is selected from the list consisting of Thiamine, Pyridoxine Hydrochloride, and Cyanocobalamin or any combination thereof.
    [11 ]
    eleven . The composition according to any of claims 1-10, wherein the Thiamine (Vitamin 81) is in a concentration of between 10 and 250 milligrams per 15 ml of the total volume of the preparation (w / v).
    [12]
    12. The composition according to any of claims 1-11, wherein the Thiamine (Vitamin 81) is in a concentration of 100 milligrams per 15 ml of the total volume of the preparation (w / v).
    [13]
    13. The composition according to any of claims 1-12, wherein the Pyridoxine Hydrochloride (Vitamin 86) is in a concentration of between 30 and 500 milligrams per 15 ml of the total volume of the preparation (w / v).
    [14]
    14. The composition according to any of claims 1-13, wherein the Pyridoxine Hydrochloride (Vitamin 86) is in a concentration of 300 milligrams per 15 ml of the total volume of the preparation (plv).
    [15]
    fifteen. The composition according to any of claims 1-14, wherein the Cyanocobalamin (Vitamin 812) is in a concentration of between 0.5 and 5 milligrams per 15 ml of the total volume of the preparation (w / v).
    [16]
    16. The composition according to any of claims 1-15, wherein the Cyanocobalamin (Vitamin 812) is in a concentration of between 1 and 2 milligrams per 15 ml of the total volume of the preparation (w / v).
    [17]
    17. The composition according to any of claims 1-16, wherein the composition is a pharmaceutical composition.
    [18]
    18. The composition according to any of claims 1-17, wherein the composition is contained in an opaque container.
    [19]
    19. The composition according to any of claims 1-18, wherein the composition further comprises another active ingredient selected from the list consisting of antacids, anti-flatulent, anti-nauseous, prokinetic, diuretic, analgesic, anti-migraine, local anesthetic, anti-epileptic, and antioxidant vitamins or any of its combinations.
    [20]
    twenty. The composition according to any of claims 1-19, further comprising pharmaceutically acceptable excipients.
    [21]
    twenty-one. The composition according to any of claims 1-20, wherein the pharmaceutically acceptable excipients that are selected from the list consisting of: 1M sodium hydroxide (E-524), Sodium chloride, Sodium citrate (E-331i), Creatinine , Disodium Edetate, Glycerol (E422), Sodium Hydrogen Phosphate Dihydrate, Sodium Hydrogen Carbonate, Phenol, Sodium Metabisulfite and water for injection, or any combination thereof.
    [22]
    22 The composition according to any of claims 1-21, wherein the excipients are pharmaceutically stable under extreme ambient conditions of pressure and temperature.
    [23]
    2. 3. Injectable pharmaceutical form comprising the composition according to any of claims 1-22.
    [24]
    24. The injectable pharmaceutical form according to the preceding claim, which is selected from a sterile solution, suspension, or emulsion.
    [25]
    25. The injectable pharmaceutical form according to any of claims 23-25, wherein the administration form is selected from: intramuscular (1M), intravenous (IV), or subcutaneous (SC).
    [26]
    26. The injectable pharmaceutical form according to the preceding claim, wherein the administration form is intramuscular (1M).
    [27]
    27. A combined preparation comprising:
    a) A component A: one or more corticosteroids as described in claims 2-5.
    b) A component B: one or more gastric acid suppressing agents as described in claims 6-9.
    c) A component C: at least one vitamin of group B as described in claims 10-16.
    or any of its salts esters, tautomers, solvates and hydrates, or any combination thereof.
    [28]
    28. The combined preparation according to the preceding claim, wherein the combined preparation further comprises another active ingredient that is selected from the list consisting of: antacids, anti-flatulent, anti-nauseous, prokinetic, diuretic, analgesic, anti-migraine, local anesthetic, anti-epileptic, and antioxidant vitamins or Any of your combinations.
    [29]
    29. The combined preparation according to any of claims 27-28, wherein the combined preparation further comprises pharmaceutically acceptable excipients and / or vehicles.
    [30]
    30 Pre-filled injectable device comprising the composition according to any of claims 1-22, the injectable pharmaceutical form according to any of claims 26-29, the combined preparation according to any of claims 30-32, or any combination thereof.
    [31]
    31. The pre-filled injectable device according to the preceding claim, wherein the administration form is selected from intramuscular (1M), intravenous (IV), or subcutaneous (Se).
    [32]
    32 The pre-filled injectable device according to any of claims 30-31, wherein the administration form is intramuscular (1M).
    [33]
    33. The pre-filled injectable device according to any one of claims 30-31, comprising a plastic body, a cartridge, a needle, a plunger, and a controlled release mechanism, or any combination thereof.
    [34]
    3. 4. The pre-filled injectable device according to any of claims 30-33, wherein the plastic body is flexible.
    [35]
    35 The pre-filled injectable device according to any of claims 30-34, wherein the plastic body is made of polyethylene.
    [36]
    36. The pre-filled injectable device according to any of claims 30-33, wherein the needle is covered by a protective cap.
    [37]
    37. The pre-filled injectable device according to any one of claims 30-36, wherein controlled release mechanism is activated by a metering button.
    [38]
    38. Use of the composition according to any of claims 1-22, the injectable pharmaceutical form according to any of claims 23-26, the
    36
    combined preparation according to any of claims 27-29, or the pre-filled injectable device according to any of claims 30-37, in the preparation of a medicament for the prevention, improvement, relief and / or treatment of cerebral edema.
    [39]
    39. Use of the composition, the injectable pharmaceutical form, the combined preparation or the pre-filled injectable device according to the preceding claim, wherein the cerebral edema is caused by hypoxia, trauma, hypertension, ischemia, spontaneously in genetically predisposed individuals or any combination thereof. .
    [40]
    40 Use of the composition, the injectable pharmaceutical form, the combined preparation or the pre-filled injectable device according to any of claims 38-39, wherein cerebral edema is caused by hypoxia.
    [41 ]
    41. Use of the composition, the injectable pharmaceutical form, the combined preparation or the pre-filled injectable device according to the preceding claim, wherein the hypoxia is due to exposure to great heights.
    [42]
    42 Use of the composition, the injectable pharmaceutical form, the combined preparation or the pre-filled injectable device according to any of claims 38-41, wherein the cerebral edema is due to acute mountain sickness.
    [43]
    43 Use of the composition, the injectable pharmaceutical form, the combined preparation or the pre-filled injectable device according to any of claims 38-42, wherein the administration is carried out intramuscularly (1M), intravenously (IV), or subcutaneously (Se).
    [44]
    44. Use of the composition, the injectable pharmaceutical form, the combined preparation or the pre-filled injectable device according to the preceding claim, wherein the administration is carried out intramuscularly (1M).
    [45]
    Four. Five. Use of the composition, the injectable pharmaceutical form, the combined preparation or the pre-filled injectable device according to any of claims 38-44, wherein the administration is carried out at a single dose.
    37
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    同族专利:
    公开号 | 公开日
    ES2663669B1|2019-01-23|
    WO2018050938A1|2018-03-22|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20100016265A1|2008-07-16|2010-01-21|Qaiser Yusuf|Anti-inflammatory composition and method for preparation|
    US20170304319A1|2014-11-04|2017-10-26|Acucort Ab|Dexamethasone oral film|
    CN104721202A|2015-02-09|2015-06-24|中国人民解放军西藏军区总医院|Medicine for preventing and treating acute altitude stress|
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    PCT/ES2017/070607| WO2018050938A1|2016-09-13|2017-09-12|Pre-loaded injectable device for treating cerebral edema|
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