CN103405771B - Medical composition and its use - Google Patents
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- CN103405771B CN103405771B CN201310309153.XA CN201310309153A CN103405771B CN 103405771 B CN103405771 B CN 103405771B CN 201310309153 A CN201310309153 A CN 201310309153A CN 103405771 B CN103405771 B CN 103405771B
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Abstract
The present invention proposes a kind of medical composition and its use.Described pharmaceutical composition comprises calcium channel blocker or its pharmaceutically acceptable salt, PDE5 inhibitor or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.According to the effect highly significant of pharmaceutical composition in prevention or treatment acute high altitude sickness of the embodiment of the present invention, and the combination action effect of this pharmaceutical composition in treatment altitude sickness is better than single PDE5 inhibitor, and the compositions of PDE5 inhibitor and calcium channel blocker has obvious synergistic function.
Description
Technical field
The present invention relates to medicine, particularly, relate to medical composition and its use, more specifically, relate to the pharmaceutical composition being used for the treatment of acute high altitude sickness.
Background technology
Acute high altitude sickness (acutehighaltitudedisease, AHAD) i.e. altitude sickness, be after people arrives certain height above sea level, health be that the draught head, the oxygen content that adapt to cause because of height above sea level are few, the change of air drying etc., and the natural physiological reaction produced.Clinical manifestation is headache, giddy, cyanosis, increased heart rate, gastrointestinal symptom, water-sodium retention and alkalemia etc.Altitude sickness has become the key factor of the west lags fars such as serious restriction China Qinghai-Tibet Platean development tourism, commerce and trade, production, even threatens national defense construction and the national security in China western part.
The medicine of current treatment acute high altitude sickness still can not meet clinical needs, still haves much room for improvement.
Summary of the invention
The present invention one of is intended to solve the problems of the technologies described above at least to a certain extent or at least provides a kind of useful business to select.For this reason, one object of the present invention is to provide a kind of pharmaceutical composition, and this pharmaceutical composition has the effect of prevention or treatment acute high altitude sickness.
The present invention be inventor based on following fact-finding, existing anti-Acute Altitude medicine or health food will be asked for help and a few days ago be started to take entering highlands prerequisite in the market, and road also adheres to taking, and effectively can prevent altitude sickness.But from the reaction of pill taker, the medicine of this kind of altitude sickness prevention exists two point defects: one is took these medicines in advance human body can be caused to be on wires before entering plateau, cause suitable inadaptable and side effect to people; Two is take such medicine to acute high altitude reaction almost without any effect.The unique method of current disposal acute high altitude sickness is intravenous drip, but does not in most of the cases possess corresponding medical condition, because acute high altitude sickness initiation plateau pneumochysis mortality rate is very high.
In a first aspect of the present invention, the present invention proposes a kind of pharmaceutical composition.This pharmaceutical composition comprises calcium channel blocker or its pharmaceutically acceptable salt, PDE5 inhibitor or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.According to the effect highly significant of pharmaceutical composition in prevention or treatment acute high altitude sickness of the embodiment of the present invention, and the combination action effect of this pharmaceutical composition in treatment altitude sickness is better than single PDE5 inhibitor, and the compositions of PDE5 inhibitor and calcium channel blocker has obvious synergistic function.
In a second aspect of the present invention, the present invention proposes aforementioned pharmaceutical compositions and preparing the purposes in medicine, described medicine is used for the treatment of or prevents acute high altitude sickness.Thus, this pharmaceutical composition can be effectively utilized, can body's hypoxia tolerance be improved, improve motor capacity, rapid recovery and to altitude sickness prevention, effectively prevention or treatment acute high altitude sickness.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become obvious from the following description, or be recognized by practice of the present invention.
Detailed description of the invention
Embodiments of the invention are described below in detail.It should be noted that, described embodiment is exemplary, only for explaining the present invention, and can not be interpreted as limitation of the present invention.
Embodiment according to a first aspect of the present invention proposes a kind of pharmaceutical composition.This pharmaceutical composition comprises calcium channel blocker or its pharmaceutically acceptable salt, PDE5 inhibitor or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.According to the effect highly significant of pharmaceutical composition in prevention or treatment acute high altitude sickness of the embodiment of the present invention, and the combination action effect of this pharmaceutical composition in treatment altitude sickness is better than single PDE5 inhibitor, and the compositions of PDE5 inhibitor and calcium channel blocker has obvious synergistic function.
Calcium channel blocker (CalciumChannelBlockers), also calcium antagonist (CalciumAntagonist) is, mainly through blocking the calcium channel on cardiac muscle and vascular smooth muscle cell film, the outer flow of calcium ions of T suppression cell, makes intracellular calcium level reduce and cause the medicine that the tissue organ functions such as cardiovascular change.Calcium channel blocker is to action of the heart, mainly suppress the second phase flow of calcium ions in myocardial depolarization process, reduce intracellular calcium concentration, weaken myocardial contraction, reduce myocardial oxygen consumption, suppress the Ca2+ influx of sinuatrial node and atrioventricular node simultaneously, sinus-node self-activity is declined, Atrioventricular Conduction slows down, and Ventricular Rate reduces.
Phosphodiesterase inhibitor (phosphodiesteras, PDEs) is a kind of medicine suppressing phosphodiesterase activity, mainly comprises phosphodiesterase 3,4,5 inhibitor.Wherein PDE5 inhibitor can make cGMP rising in born of the same parents will be conducive to hypertension, congestive heart failure, coronary artery disease and anginal treatment, and PDE5 inhibitor still has antiplatelet and antithrombotic acitivity.In addition, PDE5 inhibitor can reduce pulmonary artery pressure and to Heart rate influences seldom, be expected to become novel optionally dilation of the pulmonary artery agent.
According to embodiments of the invention, the dosage that effective ingredient calcium channel blocker in described pharmaceutical composition and the effective dose of PDE5 inhibitor are respectively described calcium channel blocker is 3 mg/day ~ 90 mg/day, and the dosage of described PDE5 inhibitor is 15 mg/day ~ 300 mg/day.Thus, effective ingredient is the few and air drying of draught head, oxygen content that the calcium channel blocker of above-mentioned dosage combination and phosphodiesterase inhibitor 5 compositions effectively can be alleviated human body and cause because of height above sea level and the acute high altitude sickness being symptom with headache, giddy, cyanosis, increased heart rate, gastrointestinal symptom, water-sodium retention and alkalemia caused.Inventor is surprised to find by lot of experiments, when the calcium channel blocker in aforementioned pharmaceutical compositions lower than dosage lower than the dosage of 3 mg/day or phosphodiesterase inhibitor 5 lower than 15 mg/day, the Acute Altitude disease symptoms caused by High aititude hypoxia lower pressure environment can not be alleviated, and when the calcium channel blocker in aforementioned pharmaceutical compositions lower than dosage higher than the dosage of 90 mg/day or phosphodiesterase inhibitor 5 lower than 300 mg/day, then can bring out some side reactions, human body is damaged, even dead.Preferably, the dosage of described calcium channel blocker is 15 mg/day ~ 60 mg/day, and the dosage of described calcium channel blocker is 37.5 mg/day ~ 180 mg/day.Thus, the therapeutic effect of described pharmaceutical composition without the physiological and pathological symptom of the various discomforts for the acute high altitude sickness caused by Altitude lower pressure environment can be improved further.
Term used herein " effective dose " refers to the dosage or effective dose that need be administered to patient.Described need are administered to dosage or the effective dose of patient and are easy to by those of ordinary skill in the art by using known technology and determining by observing the result obtained under similar state the frequency of administration of experimenter.When defining effective amount or effective dose, curing mainly diagnostician will consider several factors, these factors including, but not limited to, the action potency of compound used therefor and persistent period; The sex of the characteristic of disease to be treated and the order of severity and patient to be treated, age, body weight, health status and individual response and other are conditions associated.
Cell calcium oscillations has multiple, and WHO is divided into selectivity and non-selective two large classes, is wherein divided into again in selectivity cell calcium oscillations: verapamil class, nifedipine class and diltiazem class three kinds.The cell calcium oscillations being usually used in antihypertensive therapy is thought by International Union of Pharmacology, optionally act on L-type calcium channel, binding site is at α 1 subunit, and according to its concrete binding site, be divided into again four classes, comprised: bihydropyridine type (comprising nifedipine, amlodipine, nimodipine, nicardipine, nitrendipine, nisoldipine, felodipine, benidipine, lacidipine); Thiadipone class (comprising diltiazem etc.); Phenyl alkylamide (verapamil etc.); Triphen piperazines (flunarizine, cinnarizine, lidoflazine etc.).According to embodiments of the invention, the kind of calcium channel blocker is also not particularly limited, according to specific embodiments more of the present invention, described calcium channel blocker is be selected from least one in nifedipine, amlodipine, nimodipine, nicardipine, nitrendipine, nisoldipine, felodipine, benidipine, lacidipine and diltiazem.According to the preferred embodiment of the invention, described calcium channel blocker is be selected from least one in nifedipine, nimodipine, nitrendipine and nisoldipine.Thus, above-mentioned calcium channel blocker jointly can effectively be treated acute high altitude sickness or prevent as the pharmaceutical composition of the present invention of effective ingredient by combining with PDE5 inhibitor.According to most preferred embodiment of the present invention, described calcium channel blocker is nifedipine.Nifedipine be used for coronary artery dilator and peripheral arterial effect the strongest, suppress vasospasm Be very effective, be the choice drug of variant angina pectoris, be clinically applicable to angina pectoris caused by prevention and therapy angina pectoris, particularly variant angina pectoris and coronary vasospasm.Be applicable to various types of hypertension, also good therapeutic effect is had to intractable, severe hypertension, it has rapid-action, that peak/paddy ratio is high feature, there is the Ca2+ influx of Selective depression myocardial cell membrane, block myocardial cell E-C coupling, weaken the consumption that myocardial contraction reduces cardiac energy and oxygen, by preventing the direct protecting myocardial cell of calcium overload; Suppress blood vessel, the E-C coupling of bronchus and uterine smooth muscle, the effect of expansion system vascular (comprising lung, liver, kidney, brain, stock and Mesenteric artery) and arteria coronaria.Therefore, utilize nifedipine and PDE5 inhibitor to combine and jointly effectively can alleviate the symptom such as sensation of oppression over the chest with shortness of breath, dyspnea because hypoxia lower pressure environment causes as the pharmaceutical composition of the present invention of effective ingredient.
The presentation mode of the calcium channel blocker according to an embodiment of the invention in pharmaceutical composition is also not particularly limited, as long as can be compatible and form stable pharmaceutical composition with the PDE5 inhibitor in the pharmaceutical composition of the embodiment of the present invention, can mode in a variety of manners provide, according to a particular embodiment of the invention, described calcium channel blocker pharmaceutically acceptable salt is for being selected from hydrochlorate, sulfate, formates, acetate, butyrate, benzoate, fumarate, maleate, citrate, 2, 5-resorcylic acid salt, mesylate, esilate, benzene sulfonate, any one in tosilate and lauryl sulfonate.Thus, one of the effective ingredient in the pharmaceutical composition of embodiment of the present invention calcium channel blocker can hold with another effective ingredient PDE5 inhibitor in the pharmaceutical composition of the embodiment of the present invention pharmaceutical composition being combined and being formed and can effectively treat or prevent acute high altitude sickness well.
Here used term " pharmaceutically acceptable salt " means the conventional salt form of medicinal chemistry art, be namely in fact nontoxic and can provide required pharmacokinetic properties, can oral, absorb, distribution, metabolism or Excretion salt form.According to embodiments of the invention, should " pharmaceutically acceptable salt " can be common acid-addition salts or base addition salts.
5 type phosphodiesterase inhibitors are by suppressing phosphodiesterase in pulmonary arterial smooth muscle cell, increase the level of cyclic guanosine monophosphate (cGMP) in Pulmonary Vascular, endogenous NO is generated increase, thus highly selective expansion Pulmonary Vascular, reduce pulmonary vascular resistance, effectively reduce pulmonary artery pressure, increase cardiac output, and the hemodynamics of body circulation is had no significant effect.According to embodiments of the invention, described PDE5 inhibitor is be selected from least one in sldenafil, Vardenafil and tadalafil, and preferably, described PDE5 inhibitor is be selected from least one in sldenafil and Vardenafil.Thus, above-mentioned PDE5 inhibitor jointly can effectively be treated acute high altitude sickness or prevent as the pharmaceutical composition of the present invention of effective ingredient by combining with calcium channel blocker.According to most preferred embodiment of the present invention, described PDE5 inhibitor is sldenafil.Sldenafil is the medicine of a kind of oral medication male erectile dysfunction (ED) of being researched and developed by Pfizer Inc., be used for the treatment of erection disturbance and premature ejaculation, erection function is gone down and has the improvement of highly significant with premature ejaculation, it all had drug effect in 4 hours ~ 8 hours, and can onset at short notice, after 24 hours, the property of medicine excretes completely.Thus, jointly the symptom such as sensation of oppression over the chest with shortness of breath, dyspnea because hypoxia lower pressure environment causes can effectively be alleviated further as the pharmaceutical composition of the present invention of effective ingredient by utilizing calcium channel blocker and sldenafil to combine.
The presentation mode of the PDE5 inhibitor according to an embodiment of the invention in pharmaceutical composition is also not particularly limited, as long as can be compatible and form stable pharmaceutical composition with the calcium channel blocker in the pharmaceutical composition of the embodiment of the present invention, can mode in a variety of manners provide, according to a particular embodiment of the invention, described PDE5 inhibitor pharmaceutically acceptable salt is for being selected from hydrochlorate, sulfate, acetate, benzoate, fumarate, maleate, citrate, 2, 5-resorcylic acid salt, mesylate, esilate, benzene sulfonate, tosilate, lauryl sulfonate, any one in Dobesilate and hydrobromate.Thus, one of the effective ingredient in the pharmaceutical composition of embodiment of the present invention PDE5 inhibitor can hold with another effective ingredient calcium channel blocker in the pharmaceutical composition of the embodiment of the present invention pharmaceutical composition being combined and being formed and can effectively treat or prevent acute high altitude sickness well.
According to some specific embodiments of the present invention, described pharmaceutical composition can comprise and is selected from following at least one group: nifedipine and sldenafil; Nimodipine and sldenafil; Nitrendipine and sldenafil; Nisoldipine and sldenafil; Nifedipine and Vardenafil; Nimodipine and Vardenafil; Nitrendipine and Vardenafil; And nisoldipine and Vardenafil.According to most preferred embodiment of the present invention, described pharmaceutical composition can be nifedipine and sldenafil.Thus, the Acute Altitude disease of the symptoms such as the sensation of oppression over the chest with shortness of breath that causes due to high altitude low air pressure effectively can must be alleviated with the calcium channel blocker of combinations thereof and PDE5 inhibitor.
Particularly, nifedipine can reduce pulmonary artery pressure effectively, improves pulmonary circulation, improves the heart, pulmonary function, thus improves the symptoms such as uncomfortable in chest, out of breath.Sldenafil has enhancing human body resisting fatigue and antioxidative effect, expansible Pulmonary Vascular, increase gas exchange, reduction oxygen consumption.The two combination, can improve body's hypoxia tolerance, improves motor capacity, rapid recovery and to altitude sickness prevention, effectively prevention or treatment acute high altitude sickness.And, nifedipine and the collaborative use of these two kinds of medicines of sldenafil, more more obvious than the effect be used alone, that is: there is synergistic function between nifedipine and sldenafil.
Zoopery shows, the life span of compositions after Acute Hypoxic Animals of nifedipine and sldenafil is significantly longer than Normal group and Nifedipine group, illustrate that pharmaceutical composition of the present invention has and improve the effect of body's hypoxia tolerance, and than the better effects if of single nifedipine and single sldenafil.
Animal acute toxicity experiment proves, the pharmaceutical composition of nifedipine and sldenafil obvious impact is not produced on every important indicators such as rat holistic health, biochemical functions and organ-tissue morphologys, show that compositions of the present invention takes safety.
Acute high altitude reaction person takes compound tablet of the present invention, obviously can alleviate related symptoms, and in about 30 minutes, user is dizzy, headache, nervous, symptom disappear substantially, and most user's tachypnea, weak, nauseating, dim eyesight, vertigo symptoms disappear substantially; Physiology sign is improved main manifestations and is decreased heart rate, breathes mild, lip and turn red, and sign performance is all tending towards normal.Different according to the physical condition of user, onset time is slightly different, but most user is taking in about 30 minutes, and altitude sickness is all effectively alleviated.Further, after taking nifedipine of the present invention and sldenafil compositions, behind radical 5000m plateau, heart rate increasing degree significantly reduces, blood oxygen saturation fall significantly reduces.
According to embodiments of the invention, in pharmaceutical composition nifedipine and sldenafil ratio and be not particularly limited, according to concrete example of the present invention, the weight ratio of nifedipine and sldenafil is 1:0.5 ~ 20.Inventor is surprised to find, and when the weight ratio of nifedipine and sldenafil is with higher than 1:0.5 or when combining lower than the proportioning of 1:20, pharmaceutical composition all can not reach desirable effect for the mitigation of the various symptoms of acute high altitude sickness.According to the preferred embodiment of the invention, the weight ratio of nifedipine and sldenafil is 1:2.5 ~ 10, and the effect that the pharmaceutical composition that ratio carries out combining according to this alleviates acute high altitude sickness can be further enhanced.According to the preferred embodiment of the present invention, the weight ratio of nifedipine and sldenafil is 1:3.75, inventor is found by the contrast of great many of experiments, and when nifedipine and sldenafil combine with the weight ratio of 1:3.75, the effect of the treatment acute high altitude sickness of its symptom is the most remarkable.In addition, we also find, pharmaceutical composition of the present invention, under the prerequisite ensureing curative effect, reduce the dosage of nifedipine and these two kinds of active component of sldenafil, to acute high altitude sickness, there is good therapeutical effect, also can reduce the side effect relevant to these active substances.
According to embodiments of the invention, effective active composition in pharmaceutical composition of the present invention can make solid preparation or liquid forms with multiple pharmaceutically acceptable mixed with excipients, as solid forms such as tablet, capsule, granule or powder agents, or the liquid form such as oral liquid, injection.According to a particular embodiment of the invention, preferred dosage form is tablet, granule, capsule, but is not limited to described preferred dosage form, also comprises other pharmaceutically conventional oral formulations.Wherein tablet, granule, capsule can be ordinary preparations, also can be the use of the sustained-release preparation of special technique.When being prepared into the solid composition preparation of granular form, Sugarless type can being made or have sugar-type.Thus, the patient suffering from Acute Altitude disease symptom can carry and take pharmaceutical composition of the present invention easily, thus plays prevention and therapy effect timely.
Term " pharmaceutically acceptable excipient " used here can comprise any pharmaceutically operable common excipients, such as, for controlling the framework material (namely rate of release is adjusted) etc. of active component rate of release in disintegrating agent, binding agent, filler, lubricant, sustained-release preparation, make it have slow release or controlled release activity, make the active component of its sustained release scheduled volume.
According to embodiments of the invention, disintegrating agent includes but not limited to starch, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, low substituted carboxymethyl sodium cellulosate, alginic acid.
According to embodiments of the invention, binding agent includes but not limited to polyvinylpyrrolidone, hydroxypropyl cellulose, hypromellose, starch slurry, gelatin, sodium alginate.
According to embodiments of the invention, filler includes but not limited to lactose, pre-paying starch, microcrystalline Cellulose, calcium carbonate, calcium hydrogen phosphate, starch, glycine, sucrose, mannitol.
According to embodiments of the invention, lubricant includes but not limited to magnesium stearate, calcium stearate, Pulvis Talci, micropowder silica gel.
According to embodiments of the invention, the framework material of rate of release regulator includes but not limited to hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, polyoxyethylene.
According to embodiments of the invention, when pharmaceutical composition provides with tablet form, every 1000 tablets of tablets comprise: nifedipine 2 grams ~ 40 grams; Sldenafil 10 grams ~ 200 grams; Disintegrating agent 5 grams ~ 50 grams; Filler 20 grams ~ 300 grams; Binding agent 2 grams ~ 40 grams, and described tablet comprises the lubricant of 0.3 ~ 1.0 % by weight further.
According to embodiments of the invention, pharmaceutical composition of the present invention can further containing the framework material etc. for controlling active component rate of release, pharmaceutical composition is made to have slow release or controlled release activity, can the active component of sustained release scheduled volume, make slow releasing tablet or controlled release tablet.According to a particular embodiment of the invention, when pharmaceutical composition provides with tablet form, every 1000 tablets of tablets comprise: nifedipine 2 grams ~ 40 grams; Sldenafil 10 grams ~ 200 grams; Disintegrating agent 5 grams ~ 50 grams; Filler 20 grams ~ 300 grams; Binding agent 2 grams ~ 40 grams; Rate of release regulator 5 grams ~ 50 grams, and described tablet comprises the lubricant of 0.3 ~ 1.0 % by weight further.Preferably, wherein rate of release regulator be incorporated as 10 grams ~ 30 grams.
According to the present invention's preferred embodiment, every 1000 tablets of tablets that consist of of tablet formulation comprise: nifedipine 5 grams ~ 25 grams; Sldenafil 12.5 grams ~ 100 grams; Cross-linking sodium carboxymethyl cellulose 10 grams ~ 40 grams; Lactose 50 grams ~ 180 grams; Microcrystalline Cellulose 10 grams ~ 40 grams; Pre-paying starch 10 grams ~ 40 grams; Magnesium stearate 0.3 gram ~ 5 grams, and 10% starch slurry 5 grams ~ 30 grams.
According to embodiments of the invention, prepare the method for tablet and be not particularly limited, the technology of preparing of this area routine can be used, the active component of pharmaceutical composition of the present invention is controlled at 100 order ~ 200 orders.According to some embodiments of the present invention, the method preparing tablet can adopt dry roll the granulation techniques such as method, wet method or sulfuration spraying granulate after tabletting, also can adopt after pharmaceutical composition is is directly pulverized and sieved and carry out tabletting.According to other embodiments of the present invention, can single-layer sheet be prepared into, also can make the flap-type well known in the art such as double-layer tablet and slow-release tablet.According to a particular embodiment of the invention, outside label can film coating layer or sugar-coat clothing layer also can not film coating layer or sugar-coat clothing layer.In addition, in the preparation of tablet, also appropriate correctives can be added according to needs, to cater to the demand of different mouthfeel.
According to embodiments of the invention, when pharmaceutical composition provides with Capsule form, every 1000 seed lac wafers comprise: nifedipine 2 grams ~ 40 grams; Sldenafil 10 grams ~ 200 grams; Disintegrating agent 5 grams ~ 60 grams; Filler 20 grams ~ 280 grams; Binding agent 10 grams ~ 50 grams, and described capsule comprises the lubricant of 0.3 ~ 1.0 % by weight further.
According to embodiments of the invention, pharmaceutical composition of the present invention can further containing the framework material etc. for controlling active component rate of release, pharmaceutical composition is made to have slow release or controlled release activity, can the active component of sustained release scheduled volume, make slow releasing capsule or controlled release capsule.According to a particular embodiment of the invention, when pharmaceutical composition provides with Capsule form, every 1000 seed lac wafers comprise: nifedipine 2 grams ~ 40 grams; Sldenafil 10 grams ~ 200 grams; Disintegrating agent 5 grams ~ 60 grams; Filler 20 grams ~ 280 grams; Binding agent 10 grams ~ 50 grams; Rate of release regulator 3 grams ~ 40 grams, and described capsule comprises the lubricant of 0.3 ~ 1.0 % by weight further.Preferably, wherein rate of release regulator be incorporated as 10 grams ~ 30 grams.
According to the present invention's preferred embodiment, every 1000 seed lac wafers that consist of of capsule formula comprise: nifedipine 5 grams ~ 25 grams; Sldenafil 12.5 grams ~ 100 grams; Hypromellose 10 grams ~ 40 grams; Lactose 30 grams ~ 200 grams; Pre-paying starch 40 grams ~ 80 grams; And magnesium stearate 0.3 gram ~ 5 grams.
According to embodiments of the invention, prepare the method for capsule and be not particularly limited, the technology of preparing of this area routine can be used, the active component of pharmaceutical composition of the present invention is controlled at 100 order ~ 200 orders.According to some embodiments of the present invention, the method preparing capsule can adopt dryly rolls the granulation techniques such as method, wet method or sulfuration spraying to make suitable size particles encapsulated again, also can adopt pharmaceutical composition directly pulverized and sieved after mix homogeneously encapsulated.
According to embodiments of the invention, when pharmaceutical composition provides with granular form, every 1000 bags of granules comprise: nifedipine 2 grams ~ 40 grams; Sldenafil 10 grams ~ 200 grams; Disintegrating agent 5 grams ~ 60 grams; Filler 30 grams ~ 280 grams; Binding agent 5 grams ~ 40 grams, and described granule comprises the lubricant of 0.3 ~ 1.0 % by weight further.
According to embodiments of the invention, pharmaceutical composition of the present invention can further containing the framework material etc. for controlling active component rate of release, pharmaceutical composition is made to have slow release or controlled release activity, can the active component of sustained release scheduled volume, make slow-releasing granules and controlled release granule.According to a particular embodiment of the invention, when pharmaceutical composition provides with granular form, every 1000 bags of granules comprise: nifedipine 2 grams ~ 40 grams; Sldenafil 10 grams ~ 200 grams; Disintegrating agent 5 grams ~ 60 grams; Filler 30 grams ~ 280 grams; Binding agent 5 grams ~ 40 grams; Rate of release regulator 3 grams ~ 40 grams, and described granule comprises the lubricant of 0.3 ~ 1.0 % by weight further.Preferably, wherein rate of release regulator be incorporated as 10 grams ~ 30 grams.
According to the present invention's preferred embodiment, every 1000 bags of granules that consist of of Granular formulations comprise: nifedipine 5 grams ~ 25 grams; Sldenafil 12.5 grams ~ 100 grams; Hypromellose 8 grams ~ 40 grams; Lactose 40 grams ~ 220 grams; Starch 50 grams ~ 100 grams; And magnesium stearate 0.3 gram ~ 5 grams.
According to embodiments of the invention, prepare the method for granule and be not particularly limited, the technology of preparing of this area routine can be used, the active component of pharmaceutical composition of the present invention is controlled at 100 order ~ 200 orders.According to some embodiments of the present invention, the method preparing granule can adopt dryly roll method, wet method makes suitable particulate.According to a particular embodiment of the invention, when making slow, controlled release granule, in the composition of above-mentioned capsule, adding framework material or wrap slow, release-controlled film, making slow, controlled release granule, encapsulate to obtain granule.
Thus, the invention provides a kind of pharmaceutical composition of the anti-acute high altitude sickness containing calcium channel blocker, PDE5 inhibitor and pharmaceutically acceptable excipient, said composition has the effect of excellent prevention or treatment acute high altitude sickness, can be used as preventive drug or the curative of acute high altitude sickness, be used for preventing or the generation for the treatment of acute high altitude sickness event.
Embodiment according to a second aspect of the present invention provides aforementioned pharmaceutical compositions and is preparing the purposes in medicine, and described medicine is used for the treatment of or prevents acute high altitude sickness.
According to pharmaceutical composition of the present invention, may be used for improving body's hypoxia tolerance, improve motor capacity, rapid recovery and to altitude sickness prevention, effectively prevention or treatment acute high altitude sickness.And nifedipine and these two kinds of medicines of sldenafil are collaborative to be used, more more obvious than being used alone nifedipine and being used alone the effect of sldenafil, that is: there is synergistic function between nifedipine and sldenafil.After acute high altitude reaction person takes compound preparation of the present invention, obviously can alleviate the related symptoms of altitude sickness, as dizzy in user, headache, nervous, symptom disappear substantially, and tachypnea, weak, nauseating, dim eyesight, vertigo symptoms disappear substantially; Physiology sign is improved main manifestations and is decreased heart rate, breathes mild, lip and turn red, and sign performance is all tending towards normal.Therefore, pharmaceutical composition of the present invention has good Clinical practice and is worth, and can improve the compliance of patient's medication, improve clinical drug safety and curative effect, can also reduce costs simultaneously, alleviate altitude sickness patient burden, there is good economic benefit and social benefit.
The drug compatibility of embodiment 1 nifedipine and sldenafil is tested
Under these two kinds of medicines of nifedipine and sldenafil being prepared and are stored in 3 kinds of different temperature humidity conditions, i.e. 25 degrees Celsius/10%RH; 30 degrees Celsius/60%RH; 40 degrees Celsius/75%RH.Mixing group and unmixed group is divided into by medicine to compare, under being placed in these three kinds of temperature respectively.Sample carried out the evaluation of color, physical behavior, chemical stability (passing through chromatographer) at the 1st day, the 2nd day, the 7th day, the 14th day, the 30th day, the degree (% mixing group/% matched group) of each active component activation recovering under all storage requirement, nifedipine is 96.0% ~ 103.5%, and sldenafil is 97.1% ~ 104.2%.In observation, mixing group and matched group are analyzed without significant difference at physical form and chemical colour system method, and after the compositions mixing of these two kinds of medicines is described, the physical property of the two and chemical still have the good compatibility.
Embodiment 2 is containing the compound tablet of nifedipine 10 milligrams with sldenafil 37.5 milligrams
After the nifedipine of 10 grams, the sldenafil of 37.5 grams were pulverized 120 mesh sieves respectively, with cross the cross-linking sodium carboxymethyl cellulose of 25 grams of 80 mesh sieves, the lactose of 100 grams, the microcrystalline Cellulose of 20 grams, the pre-paying starch of 15 grams mixs homogeneously, add the 10% starch slurry soft material of 30 grams, cross 24 mesh sieves to granulate, then aeration-drying at 50 c, and after using 20 mesh sieve granulate, mix homogeneously with the magnesium stearate of 3 grams, tabletting, obtains medicinal composition tablets A.
Embodiment 3 is containing the compound tablet of nifedipine 10 milligrams with sldenafil 37.5 milligrams
The nifedipine of 10 grams was pulverized 150 mesh sieves, mix homogeneously with the cross-linking sodium carboxymethyl cellulose of 12 grams, the lactose of 30 grams of crossing 80 mesh sieves, add the 2% hypromellose soft material of 2 grams, cross 24 mesh sieves to granulate, then aeration-drying at 50 c, mix homogeneously with the magnesium stearate of 0.3 gram after 20 mesh sieve granulate, obtain granule 1 for subsequent use.
The sldenafil of 37.5 grams was pulverized 150 mesh sieves, with cross the cross-linking sodium carboxymethyl cellulose of 28 grams of 80 mesh sieves, the lactose of 50 grams, the microcrystalline Cellulose of 15 grams, the starch of 36 grams mixs homogeneously, add the 2% hypromellose soft material of 5 grams, cross 24 mesh sieves to granulate, then aeration-drying at 50 c, mix homogeneously with the magnesium stearate of 2 grams after 20 mesh sieve granulate, obtain granule 2 for subsequent use.
Adopt Double layer pellet technology that granule 1 and granule 2 are pressed into double-layer tablet, obtain medicinal composition tablets B.
The evaluation of embodiment 4 tablet
Embodiment 2, embodiment 3 prepare sample by different technique, and in preparation process, its mobility of particle, tablet hardness, friability, disintegration are all more satisfactory, the results are shown in Table 1.
Table 1
Embodiment 5 is containing the compound capsule of nifedipine 10 milligrams with sldenafil 37.5 milligrams
After the nifedipine of 10 grams, the sldenafil of 37.5 grams were pulverized 120 mesh sieves respectively, with cross the hypromellose of 15 grams of 80 mesh sieves, the lactose of 80 grams, the pre-paying starch of 50 grams, the magnesium stearate of 2 grams mix homogeneously, fill, obtains medicament composition capsule agent.
Embodiment 6 is containing the compound granule of nifedipine 10 milligrams with sldenafil 37.5 milligrams
The nifedipine of 10 grams, the sldenafil of 37.5 grams were pulverized 120 mesh sieves respectively, then with cross the hypromellose of 25 grams of 80 mesh sieves, the lactose of 130 grams, the starch of 70 grams mixs homogeneously, dry rolling granulating, choose granule between 20 order ~ 40 mesh sieves, mix homogeneously with the magnesium stearate of 2 grams, obtain medicament composition granule agent A.
Embodiment 7 is containing the compound granule of nifedipine 10 milligrams with sldenafil 50 milligrams
The nifedipine of 10 grams was pulverized 120 mesh sieves, with cross the cross-linking sodium carboxymethyl cellulose of 20 grams of 80 mesh sieves, the lactose of 50 grams, the microcrystalline Cellulose of 8 grams, the starch of 20 grams mixs homogeneously, add the 5% PVP K30 soft material of 0.5 gram, 14 mesh sieves are granulated, 50 degrees Celsius of aeration-dryings, choose granule between 20 order ~ 40 mesh sieves, obtain granule 3 for subsequent use.
The sldenafil of 50 grams was pulverized 120 mesh sieves, with cross the cross-linking sodium carboxymethyl cellulose of 40 grams of 80 mesh sieves, the lactose of 100 grams, the microcrystalline Cellulose of 20 grams, the starch of 60 grams mixs homogeneously, add the 5% PVP K30 soft material of 2 grams, 14 mesh sieves are granulated, 50 degrees Celsius of aeration-dryings, choose granule between 20 order ~ 40 mesh sieves, obtain granule 4 for subsequent use.
After granule 3, granule 4 being mixed homogeneously with the magnesium stearate of 3.5 grams, obtain medicament composition granule agent B.
The evaluation of embodiment 8 granule
Detect the medicament composition granule agent that embodiment 6 and 7 is made, wherein between 20 order ~ 40 mesh sieves, granule accounts for 86% and 88% respectively, detects granule entirely molten, meet the requirements by soluble particles inspection technique.
Embodiment 9 present composition is to the acute anoxia enduring experiment of mice
By 70 body weight, 25 ± 2 grams of healthy male mouse of kunming, be divided into 6 groups at random, often organize 12.Comprising A group: Normal group; B group: nifedipine (3.5mgkg
-1); C group: sldenafil (12.0mgkg
-1); D group: nifedipine-sldenafil pharmaceutical composition low dosage (1.75/6.0mgkg
-1); E group: dosage (3.5/12.0mgkg in nifedipine-sldenafil pharmaceutical composition
-1); F group: nifedipine-sldenafil pharmaceutical composition high dose (7.0/24.0mgkg
-1).A group gavage every day distilled water, B group-F group respectively in gavage mode to mice feed with the medicinal liquid of 0.5% sodium carboxymethyl cellulose suspendible, totally 10 days.The 11st day time, mice is put into the 250mL wide mouthed bottle being lined with sodica calx, every bottle of Mus, covers tightly with the rubber closure scribbling vaseline, the manual time-keeping mouse survival time.A group, the B group life span after Acute Hypoxic Animals experiment is without obvious prolongation, and C group, D group, E group, the F group life span after Acute Hypoxic Animals experiment is significantly longer than normal control A group, and D group, E group, F group are longer than the life span of C group.Illustrate that pharmaceutical composition of the present invention has and improve the effect of body's hypoxia tolerance, and than the better effects if of single nifedipine and single sldenafil.
During zoopery, each treated animal body weight change does not have significant change.Known from the result shown in table 2, A group, the B group life span after Acute Hypoxic Animals experiment is without obvious prolongation, C group, D group, E group, the F group life span after Acute Hypoxic Animals experiment is significantly longer than normal control A group, and D group, E group, F group are longer than the life span of C group.Illustrate that pharmaceutical composition of the present invention has and improve the effect of body's hypoxia tolerance, and than the better effects if of single nifedipine and single sldenafil.
The each group of comparison to chmice acute anoxia enduring life span tested by table 2
Compare with Normal group, * P<0.05; Compare with Normal group, *
△p<0.01
Embodiment 10 human trial one
Nifedipine-sldenafil compound tablet the A prepared by embodiment 2 is taken to acute high altitude reaction crowd in certain limit, effect shows: acute high altitude reaction person takes compound tablet A of the present invention, obviously can alleviate related symptoms, in about 30 minutes, user is dizzy, headache, nervous, symptom disappear substantially, and most user's tachypnea, weak, nauseating, dim eyesight, vertigo symptoms disappear substantially; Physiology sign is improved main manifestations and is decreased heart rate, breathes mild, lip and turn red, and sign performance is all tending towards normal.Different according to the physical condition of user, onset time is slightly different, but most user is taking in about 30 minutes, and altitude sickness is all effectively alleviated.
Embodiment 11 human trial two
68 ages are divided into two groups at the health young man of 18 years old ~ 30 years old, often organize 34 people.Adopt double-blind method, the order of height above sea level 3500 meters of wherein one group take placebo (matched group), another group takes tablet A (group of taking medicine) prepared by the embodiment of the present invention 2, after taking medicine continuously 20 days, two groups all radical to 5000m height above sea level, and measure heart rate and blood oxygen saturation after one day.
Table 3 invention formulation affects changes in heart rate
As seen from the results in Table 3, after taking present composition tablet, behind radical 5000m plateau, heart rate increasing degree significantly reduces.
Table 4 invention formulation affects blood oxygen saturation
As seen from the results in Table 4, after taking present composition tablet, behind radical 5000m plateau, experimenter's blood oxygen saturation fall significantly reduces.
In the description of this description, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification.
Claims (26)
1. a pharmaceutical composition, is characterized in that, comprises:
Calcium channel blocker or its pharmaceutically acceptable salt;
PDE5 inhibitor or its pharmaceutically acceptable salt;
And pharmaceutically acceptable excipient,
Wherein,
The dosage of described calcium channel blocker is 3 mg/day ~ 90 mg/day, and the dosage of described PDE5 inhibitor is 15 mg/day ~ 300 mg/day,
Described calcium channel blocker is nifedipine,
Described PDE5 inhibitor is sldenafil,
Described pharmaceutical composition is used for the treatment of or prevents acute high altitude sickness,
The weight ratio of nifedipine and sldenafil is 1:2.5 ~ 10.
2. pharmaceutical composition according to claim 1, is characterized in that, the dosage of described calcium channel blocker is 15 mg/day ~ 60 mg/day, and the dosage of described PDE5 inhibitor is 37.5 mg/day ~ 180 mg/day.
3. pharmaceutical composition according to claim 1, it is characterized in that, described calcium channel blocker pharmaceutically acceptable salt be selected from hydrochlorate, sulfate, formates, acetate, butyrate, benzoate, fumarate, maleate, citrate, DHB salt, mesylate, esilate, benzene sulfonate, tosilate and lauryl sulfonate any one.
4. pharmaceutical composition according to claim 1, it is characterized in that, described PDE5 inhibitor pharmaceutically acceptable salt be selected from hydrochlorate, sulfate, acetate, benzoate, fumarate, maleate, citrate, DHB salt, mesylate, esilate, benzene sulfonate, tosilate, lauryl sulfonate, Dobesilate and hydrobromate any one.
5. pharmaceutical composition according to claim 1, is characterized in that, the weight ratio of nifedipine and sldenafil is 1:3.75.
6. pharmaceutical composition according to claim 1, is characterized in that, described pharmaceutical composition is solid dosage form or liquid forms.
7. pharmaceutical composition according to claim 1, is characterized in that, described pharmaceutical composition is at least one form in tablet, granule, capsule, slow releasing preparation and controlled release preparation.
8. pharmaceutical composition according to claim 1, is characterized in that, described pharmaceutically acceptable excipient comprises disintegrating agent, binding agent, filler, lubricant, rate of release regulator.
9. pharmaceutical composition according to claim 8, is characterized in that, described disintegrating agent comprises starch, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, low substituted carboxymethyl sodium cellulosate and alginic acid.
10. pharmaceutical composition according to claim 8, is characterized in that, described binding agent comprises polyvinylpyrrolidone, hydroxypropyl cellulose, hypromellose, starch slurry, gelatin and sodium alginate.
11. pharmaceutical compositions according to claim 8, is characterized in that, described filler comprises lactose, pregelatinized Starch, microcrystalline Cellulose, calcium carbonate, calcium hydrogen phosphate, starch, glycine, sucrose, mannitol.
12. pharmaceutical compositions according to claim 8, is characterized in that, described lubricant comprises magnesium stearate, calcium stearate, Pulvis Talci, micropowder silica gel.
13. pharmaceutical compositions according to claim 8, is characterized in that, described rate of release regulator comprises hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, polyoxyethylene.
14. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with tablet form, and wherein, every 1000 tablets of tablets comprise:
And described tablet comprises the lubricant of 0.3 ~ 1.0 % by weight further.
15. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with tablet form, and wherein, every 1000 tablets of tablets comprise:
And described tablet comprises the lubricant of 0.3 ~ 1.0 % by weight further.
16. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with tablet form, and wherein, every 1000 tablets of tablets comprise:
And described tablet comprises the lubricant of 0.3 ~ 1.0 % by weight further.
17. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with tablet form, and wherein, every 1000 tablets of tablets comprise:
18. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with Capsule form, and wherein, every 1000 seed lac wafers comprise:
And described capsule comprises the lubricant of 0.3 ~ 1.0 % by weight further.
19. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with Capsule form, and wherein, every 1000 seed lac wafers comprise:
And described capsule comprises the lubricant of 0.3 ~ 1.0 % by weight further.
20. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with Capsule form, and wherein, every 1000 seed lac wafers comprise:
And described capsule comprises the lubricant of 0.3 ~ 1.0 % by weight further.
21. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with Capsule form, and wherein, every 1000 seed lac wafers comprise:
22. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with granular form, and wherein, every 1000 bags of granules comprise:
And described granule comprises the lubricant of 0.3 ~ 1.0 % by weight further.
23. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with granular form, and wherein, every 1000 bags of granules comprise:
And described granule comprises the lubricant of 0.3 ~ 1.0 % by weight further.
24. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with granular form, and wherein, every 1000 bags of granules comprise:
And described granule comprises the lubricant of 0.3 ~ 1.0 % by weight further.
25. pharmaceutical compositions according to claim 1, is characterized in that, described pharmaceutical composition provides with granular form, and wherein, every 1000 bags of granules comprise:
26. pharmaceutical compositions according to any one of claim 1 ~ 25 are preparing the purposes in medicine, and described medicine is used for the treatment of or prevents acute high altitude sickness.
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| CN201310309153.XA CN103405771B (en) | 2013-07-22 | 2013-07-22 | Medical composition and its use |
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2013
- 2013-07-22 CN CN201310309153.XA patent/CN103405771B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Vardenafil, but not sildenafil or tadalafil, has calcium-channel blocking activity in rabbit isolated pulmonary artery and human washed platelets;HA Toque etal;《British Journal of Pharmacology》;20080421;第154卷;第787-796页 * |
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