CN102302476B - Dehydrobufotenine dry power inhaler and preparation method and application thereof - Google Patents
Dehydrobufotenine dry power inhaler and preparation method and application thereof Download PDFInfo
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- CN102302476B CN102302476B CN 201110147769 CN201110147769A CN102302476B CN 102302476 B CN102302476 B CN 102302476B CN 201110147769 CN201110147769 CN 201110147769 CN 201110147769 A CN201110147769 A CN 201110147769A CN 102302476 B CN102302476 B CN 102302476B
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- dehydrobufotenine
- lactose
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- microns
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Abstract
The invention relates to a dehydrobufotenine dry power inhaler, in particular to a dry power inhaler made of dehydrobufotenine, a preparation method of the dry power inhaler and application of the dry power inhaler in preparation of drugs for treating tumors of lung. The dehydrobufotenine dry power inhaler is characterized by consisting of the dehydrobufotenine and medically acceptable auxiliary materials, and the mass ratio of the dehydrobufotenine to the medically acceptable auxiliary materials is 1: 0.02 - 1:100. The dehydrobufotenine is prepared to be the dry powder inhaler, therefore, the dehydrobufotenine can be directly acted on pulmonary lesions, the happening of adverse actions is reduced, the bioavailability of the drug is enhanced, the defects of oral formulation including sloweffect, first-pass effect to liver, low bioavailability and the like are overcome, and synchronously the problems of injection including inconvenience for use, bad compliance of patients and the likeare also solved.
Description
Technical field:
The present invention relates to Foradil Aerolizer formoterol fumarate, specifically the preparation method of the Foradil Aerolizer formoterol fumarate made of dehydrobufotenine, described Foradil Aerolizer formoterol fumarate and the application in preparation treatment lung tumors medicine.
Background technology:
Cutis Bufonis is the dry skin of Bufonidae animal Bufo siccus Bufobufo gargarizans Cantor, has the effect of heat-clearing and toxic substances removing, diuretic relieving distension.The Cutis Bufonis water soluble part mainly contains dehydrobufotenine, N-phenyl-ethylnaphthalene amine, amino acids, and wherein dehydrobufotenine is the indole alkaloids, is its main component, and molecular formula is C
12H
14N
2O, antitumor activity in vitro show that dehydrobufotenine has tumors of higher and suppresses active.Serve as the existing a plurality of listings of medicine of main exploitation with water soluble ingredient in the Cutis Bufonis, cinobufacin injection, oral liquid, tablet have been applied to clinically at present, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had curative effect preferably.Especially HUACHANSU ZHUSHEYE, be from the water soluble preparation of Bufo siccus skin through being processed into, treatment primary hepatocarcinoma and medium and advanced lung cancer obtain 44% and 56% comprehensive effective percentage respectively, and tumor body minification is respectively 10% and 16%, and chemotherapy and radiation is had synergism.But injection need use in hospital, the administering mode costliness, and patient compliance is poor, is difficult to carry out long-term treatment.In addition, though the clinical untoward reaction of HUACHANSU ZHUSHEYE is less, but still exist the intravenous drip meeting local vein reaction to occur, cause that the instillation vein shrinks spasm and causes pain, long-time stimulus causes the vein nonspecific inflammation; Dermoreaction mainly shows as the infringement of urticaria and skin blister sample; Secondly, cardiovascular system reactions such as premature beat, sinus bradycardia, sinus tachycardia, atrioventricular block appear in small part patient, may be that the cardiac toxicity that a spot of bufotalin produces in the cinobufacin causes.And the cinobufacin oral formulations need be through the first pass effect of liver, and onset is slow, and the preparation bioavailability is lower.Dehydrobufotenine is one of effective ingredient in cinobufacin injection and the oral formulations, but the content in injection and oral formulations is lower; And above-mentioned preparation can not directly act on lesions position, its inhibitory action to tumor can not be performed to maximum.
Alveolar wall is made up of cell monolayer, has great surface area, make drug molecule very easily enter blood, so the lung inhalation has plurality of advantages such as rapid-action, that untoward reaction is little.(the drypowder inhalers of Foradil Aerolizer formoterol fumarate in the lung inhalation, DPIs) do not use propellant and solvent, the air-flow that produces by patient's autonomous respiration makes the medicine powder atomization, and then make drug powder be delivered to pulmonary, have and use conveniently, absorb the first mistake of rapid, no liver, rapid release, targeting location and the little characteristics of toxic and side effects, and can improve patient compliance, be specially adapted to the patient that former need carry out the long term injections treatment, be a kind of novel drug-supplying system.
The sickness rate of pulmonary carcinoma rises rapidly in worldwide, has become the first cancer killer.Present antitumor drug great majority all are drug administration by injection, and this whole body administering mode is unfavorable for drug accumulation in tumor locus, and untoward reaction increases, and cause the curative effect of medicine to reduce.
Adopt site-specific delivery of drugs that antitumor drug is transported to the tumor patient part of human body, medicine is improved in the concentration of patient part, the toxic and side effects that reduces medicine, the therapeutic effect that improves medicine are had great clinical value.Employing can directly act on dehydrobufotenine the focus of pulmonary carcinoma through the inhalant of lung administering mode, is conducive to improve dehydrobufotenine to the curative effect of pulmonary carcinoma and reduces it to the toxic and side effects of normal structure.Do not see at present the research report that the dehydrobufotenine Foradil Aerolizer formoterol fumarate with resisting tumor of lung effect is arranged.
Summary of the invention:
Goal of the invention: an object of the present invention is to provide pulmonary's dry powder inhaler formulations of dehydrobufotenine and preparation method thereof.Another object of the present invention provides the application of Foradil Aerolizer formoterol fumarate of the present invention in preparation treatment lung tumors medicine.
At the foregoing invention purpose, the invention provides following technical scheme:
A kind of dehydrobufotenine Foradil Aerolizer formoterol fumarate is characterized in that it is made up of dehydrobufotenine and medically acceptable adjuvant, and the mass ratio of dehydrobufotenine and described adjuvant is 1: 0.02-1: 100.
Described dehydrobufotenine Foradil Aerolizer formoterol fumarate is characterized in that it is to add the suction powder that adjuvant is made by dehydrobufotenine, and the particle diameter of powder is with D
50Meter is between the 0.5-1000 micron.
Described adjuvant is selected one or more mixture in sugar, alcohol, aminoacid, phospholipid, surfactant, cyclodextrin, biodegradable polymer substance, magnesium stearate, stearic acid, hard ester fumaric acid sodium, micropowder silica gel, the Pulvis Talci for use.
Described sugar can be selected one or more mixture in galactose, lactose, glucose, fructose, sucrose, trehalose, the Raffinose for use; Described alcohol can be selected one or more mixture in mannitol, xylitol, maltose alcohol, the sorbitol for use; Described aminoacid can be selected in glycine, Aspartic Acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, lysine, proline, the arginine one or more for use; Described phospholipid can be selected in soybean phospholipid, lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, the synthetic phospholipid one or more for use; Described surfactant can be selected one or more mixture in pulmonary surfactant such as dipalmitoyl phosphatidyl choline, two Laurel phosphatidyl cholines, the cholesterol for use; Described polymer substance, can select the macromolecule that meets safety requirements for use, preferred biodegradable polymer substance is one or more mixture in albumin, starch, polylactic acid, polylactic acid-glycolic guanidine-acetic acid, Polyethylene Glycol, poloxamer, hyaluronic acid, hyaluronate sodium, the sodium alginate for example.
Preferred mode is that described adjuvant is the lactose of different-grain diameter, preferred mode is that described adjuvant is for sucking the mixture with lactose granule and micronization lactose, wherein the lactose granule mean diameter is that 45-225 micron micronization lactose mean diameter is the 1-5 micron, the mass ratio of lactose granule and micronization lactose is 1020: 1-1: 1, and most preferred mode is that the mass ratio of lactose granule and micronization lactose is 100: 1-6: 1.
Described dehydrobufotenine Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Dehydrobufotenine is made powder by pulverizing or spray drying, and powder and adjuvant mix homogeneously are made to suck and are used powder, are packaged in capsule or bubble-cap or the Diskus; Perhaps with dehydrobufotenine and adjuvant mix homogeneously, make suction by pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus; Perhaps with partial supplementary material mix homogeneously in dehydrobufotenine and the prescription, make powder by pulverizing or spray drying, residue adjuvant mix homogeneously is made to suck and is used powder in powder and the prescription, is packaged in capsule or bubble-cap or the Diskus.
Preferred dehydrobufotenine Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Dehydrobufotenine by pulverizing or spray drying is made powder, is made suction with the mixture mix homogeneously of the lactose of different-grain diameter or micronization lactose and lactose and used powder, be packaged in capsule or bubble-cap or the Diskus.
The application of described dehydrobufotenine Foradil Aerolizer formoterol fumarate in preparation lung tumors medicine.
Beneficial effect:
1, lung is a kind of open organ, has great surface area, and alveolar wall is made up of cell monolayer, makes drug molecule very easily enter blood, thus the lung inhalation have rapid-action, untoward reaction is little and plurality of advantages such as easy to use.(the drypowder inhalers of Foradil Aerolizer formoterol fumarate in the lung inhalation, DPIs) do not use propellant and solvent, the air-flow that produces by patient's autonomous respiration makes the medicine powder atomization, and then make drug powder be delivered to pulmonary, have use convenient, absorb rapidly, no liver is firstly crossed, rapid release and targeting are located characteristics, be a kind of novel drug-supplying system.At present be used for the treatment of the infection of respiratory tract and pulmonary relevant for Foradil Aerolizer formoterol fumarate more, but do not see the treatment at lung tumors.Simultaneously, the research with dehydrobufotenine Foradil Aerolizer formoterol fumarate of resisting tumor of lung effect does not appear in the newspapers yet.Present Cutis Bufonis extract injection, oral liquid, tablet have been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had effect preferably.Especially HUACHANSU ZHUSHEYE, be from the water soluble preparation of Bufo siccus skin through being processed into, treatment primary hepatocarcinoma and medium and advanced lung cancer obtain 44% and 56% comprehensive effective percentage respectively, and tumor body minification is respectively 10% and 16%, and chemotherapy and radiation is had synergism.Though the clinical untoward reaction of HUACHANSU ZHUSHEYE is less, but still exist the intravenous drip meeting local vein reaction to occur, cause that the instillation vein shrinks spasm and causes pain, long-time stimulus causes the vein nonspecific inflammation; Dermoreaction mainly shows as the infringement of urticaria and skin blister sample; Secondly, cardiovascular system reactions such as premature beat, sinus bradycardia, sinus tachycardia, atrioventricular block appear in small part patient, and the possible cause of generation is the cardiac toxicity reaction that a spot of bufotalin produces in the cinobufacin.In addition, the use of injection need be used in hospital, and patient compliance is poor.Dehydrobufotenine is one of effective ingredient of cinobufacin injection and oral formulations, but the content in injection and oral formulations is lower.And above-mentioned preparation can not directly act on lesions position, dehydrobufotenine can not be performed to maximum to the inhibitory action of tumor, and oral formulations need be through the first pass effect of liver, and onset is slow, and the preparation bioavailability is lower.Using the Foradil Aerolizer formoterol fumarate of dehydrobufotenine mainly is at lung tumors, directly acts on focus, does not have liver first-pass effect simultaneously, rapid-action, and does not have above-mentioned untoward reaction, and new drug development is had very big prospect.
2, dehydrobufotenine is water soluble ingredient, and easily moisture absorption needs to be mixed into Foradil Aerolizer formoterol fumarate with adjuvant.Find in the practical operation, when dehydrobufotenine is crushed to certain particle size because of influence such as electrostatic interaction, cohesiveness between the powder, medicine and be easy to reunite, and because surface area increases, hygroscopicity strengthens, therefore need carry out proportioning with adjuvant, the problem of overcome moisture absorption, easily reuniting, the applicant is known through a large amount of experiments, dehydrobufotenine and ratio of adjuvant are controlled in particular range, and particularly adjuvant selects for use the mixture of lactose granule and micronization lactose can make the good Foradil Aerolizer formoterol fumarate of intake performance.
The specific embodiment
Below in conjunction with example the present invention is described in further detail, but scope of the present invention is not subjected to any restriction of these examples.
Embodiment 1
The preparation of inhalant: adopt comminution by gas stream to D dehydrobufotenine
90=7 microns, mix at 1: 9 by mass ratio with the lactose of particle diameter at the 45-105 micron, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 2
The preparation of inhalant: adopt comminution by gas stream to D dehydrobufotenine
90=5 microns, mix in 9: 80: 1 ratio at the leucine of 30-55 micron with lactose, the particle diameter of particle diameter at the 45-125 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 3
The preparation of inhalant: adopt comminution by gas stream to D dehydrobufotenine
90=5 microns, mix in 1: 9 ratio with the leucine of particle diameter 50-125 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 4
The preparation of inhalant: with dehydrobufotenine powder, lactose, mannitol, glycine, two Laurel phosphatidyl cholines, lecithin, magnesium stearate in 1: 5: 5: 3: 0.5: 0.5: 0.2 ratio was mixed, and comminution by gas stream is to powder D
50=7 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 5
The preparation of inhalant: with the dehydrobufotenine comminution by gas stream to powder D
90=6 microns, mix in 1: 10: 1 ratio with lactose, cholesterol, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 6
The preparation of inhalant: in dehydrobufotenine, add lactose, polyethylene glycol 6000, the albumin of 4 times, 2 times, 3 times of quality respectively, spray drying, powder D
50=9 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 7
The preparation of inhalant: dehydrobufotenine drug powder, the particle diameter of mean diameter at the 5-8 micron mixed in 10: 86: 4 ratio at mannitol, the micronization silica gel of 10-100 micron, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 8
The preparation of inhalant: dehydrobufotenine drug powder, mannitol, leucine are mixed in 9: 90: 3 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 5.5 microns powder, adding mean diameter is the lactose mixing of 125-250 micron, is packaged in capsule or bubble-cap or the Diskus, obtains inhalant.
Embodiment 9
The preparation of inhalant: dehydrobufotenine powder, mannitol, glycine are mixed in 10: 100: 5 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 6.5 microns powder, adding mean diameter is the lactose mixing of 125-250 micron, is packaged in capsule or bubble-cap or the Diskus, obtains inhalant.
Embodiment 10
1, the preparation of inhalant: with dehydrobufotenine powder (D
90=6.2 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.7 microns) mix in 6: 90: 6 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, inhalant pulmonary deposition rate is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate of dehydrobufotenine reaches 31.9%, places after 18 months under the room temperature condition, and the pulmonary deposition rate of dehydrobufotenine does not have significant change.
Embodiment 11
1, the preparation of inhalant: with dehydrobufotenine powder (D
90=6.5 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.1 microns) mix in 3: 120: 3 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, inhalant pulmonary deposition rate is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate of dehydrobufotenine reaches 29.9%, places after 18 months under the room temperature condition, and the pulmonary deposition rate of dehydrobufotenine does not have significant change.
Embodiment 12
1, the preparation of inhalant: with dehydrobufotenine powder (D
90=6.8 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.4 microns) mix in 1: 70: 1 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, inhalant pulmonary deposition rate is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate of dehydrobufotenine reaches 28.6%, places after 18 months under the room temperature condition, and the pulmonary deposition rate of dehydrobufotenine does not have significant change.
Embodiment 13
The preparation of inhalant: with dehydrobufotenine powder (D
50=7 microns), leucine (D
50=205 microns) mix in 1: 8 ratio, mix the D of back granule
50Be 226 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 14
The preparation of inhalant: dehydrobufotenine is mixed comminution by gas stream, powder D with leucine in 1: 1 ratio
90Below 5 microns, this powder is mixed with the mannitol of 9 times of amounts again, mix the D of back granule
50Be 276 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 15
The preparation of inhalant: dehydrobufotenine is mixed comminution by gas stream, powder D with poloxamer in 8: 1 ratio
90Below 8 microns, this powder is mixed with the lactose granule of 10 times of amounts, the magnesium stearate of 1 times of amount again, mix the D of back granule
50Be 421 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 16
The preparation of inhalant: with the dehydrobufotenine comminution by gas stream, powder D
90=6 microns, this powder is mixed with the lactose granule of 13 times of amounts again, mix the D of back granule
50Be 78 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 17
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment.
Effect experiment:
The method of benzopyrene percutaneous puncture pulmonary injection is set up the induced lung animal model for tumour, gets 190 of modeling rats, is divided into 19 groups at random, 10 every group.Every day 1 time, medication 7 days.The inhalant inhalation that administering mode: 1-16 group obtains for embodiment 1-16, dosage is 2mg dehydrobufotenine/kg; The 17th group of lumbar injection dehydrobufotenine, dosage is 2mg dehydrobufotenine/kg; Irritate stomach for the 18th group and give dehydrobufotenine, dosage is 2mg dehydrobufotenine/kg; The 19th group is physiology saline control group, lumbar injection 10mL/kg.Next day is put to death rat in drug withdrawal, dissects the rat lungs, observes the lung lesion situation.
Experimental result: it is 21% that the pulmonary of rat of each group of inhalant administration the incidence rate of lump or tuberosity pathological changes occurs minimum, is up to 38%; Dehydrobufotenine injection group is 58%, it is 63% that dehydrobufotenine is irritated the stomach group, the normal saline group is 100%, and each group of inhalant administration is irritated the stomach group with dehydrobufotenine injection group, dehydrobufotenine, the normal saline group has significant difference (P＜0.05) in the pulmonary lesion incidence rate.
Embodiment 18
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment.
1, the foundation of rabbit VX2 original position lung cancer model
1) the freezing cell suspension of the conventional recovery VX2 tumor of the making of lotus tumor kind rabbit makes 10
6The living cells suspension of/mL is got 1mL and is inoculated in 1 rabbit right rear leg outside intramuscular, 3 week the back can lay one's hand on and the lump of the about 30cm of a diameter in inoculation position, namely make lotus tumor kind rabbit.
2) cut the intramuscular tumor in the lotus tumor kind rabbit leg outside under the preparation aseptic condition of piece of tissue suspension, get to be and oppress the eugonic tumor tissues of sample, be cut into the mud shape.30 mesh sieves were descended in the flushing of RPMI RPMI-1640, removed individual cells and too small piece of tissue, and 20 mesh sieves were descended in the flushing of RPMI RPMI-1640 in sieve top, removed excessive piece of tissue.Get the lower part of screen branch, after the centrifugation, taking precipitate 2mL adds the RPMI RPMI-1640 and is mixed with piece of tissue suspension 20mL.
3) all rabbit right thoracic wall depilations of inoculation in the lung, intramuscular injection speed is slept and is fixed after new mixture 0.8mL/kg anaesthetizes, routine disinfection, get aseptic three way cock, connecing No. 12 injection needles, suctions respectively has the 1mL syringe of rabbit self blood clot and the syringe that suction has VX2 tumor tissue suspension or cell suspension 1mL.Under X line perspective, No. 12 syringe needles are thrust in the rabbit inferior lobe of right lung, behind the resorption depletion of blood, inject 0.4mL piece of tissue suspension or cell suspension, inject 0.2mL rabbit self blood clot then, extract syringe needle, inoculation finishes.
4) the whole rabbit of the observation of growth of xenografted situation are from inoculating back the 3rd day, and carry out layer wide, bed thickness be 5mm CT scan to chest every day, observes transfer case in tumor growth, the thoracic cavity.
5) rabbit VX2 original position lung cancer model is set up as a result rabbit all tumor growth in the lung, success ratio of inoculation 100%.
2, pharmacodynamic experiment
Get successfully 190 of modeling rabbit, be divided into 19 groups at random, 10 every group.Every day 1 time, medication 12 days.The inhalant inhalation that administering mode: 1-16 group obtains for embodiment 1-16, dosage is 2mg dehydrobufotenine/kg; The 17th group of lumbar injection dehydrobufotenine, dosage is 2mg dehydrobufotenine/kg; Irritate stomach for the 18th group and give dehydrobufotenine, dosage is 2mg dehydrobufotenine/kg; The 19th group is physiology saline control group, lumbar injection 10mL/kg.Next day is put to death rabbit in drug withdrawal, dissects the rabbit lungs, peels off tumor tissues, weighs.
Experimental result: the tumour inhibiting rate minimum of each group of inhalant administration is 45.1%, is up to 58.2%; The tumour inhibiting rate of dehydrobufotenine injection group is 33.6%, the tumour inhibiting rate that dehydrobufotenine is irritated the stomach group is 28.5%, normal saline does not almost have inhibitory action to tumor, and each group of inhalant administration has significant difference (P＜0.05) with the tumour inhibiting rate that dehydrobufotenine injection group, dehydrobufotenine are irritated stomach group, normal saline group.
Claims (3)
1. a dehydrobufotenine Foradil Aerolizer formoterol fumarate is characterized in that it is by D
90Be that 6.2 microns dehydrobufotenine powder, German U.S. agent are happy
Lactose and D
90The micronization lactose that is 5.7 microns was formed by 6: 90: 6; Perhaps by D
90Be that 6.5 microns dehydrobufotenine powder, German U.S. agent are happy
Lactose and D
90The micronization lactose that is 5.1 microns was formed by 3: 120: 3; Perhaps by D
90Be that 6.8 microns dehydrobufotenine powder, German U.S. agent are happy
Lactose and D
90The micronization lactose that is 5.4 microns was formed by 1: 70: 1.
2. method for preparing the described dehydrobufotenine Foradil Aerolizer formoterol fumarate of claim 1, its preparation process is as follows:
Dehydrobufotenine is made powder by pulverizing or spray drying, with
Be packaged in capsule or bubble-cap or the Diskus behind lactose and the micronization lactose mix homogeneously, obtain inhalant.
3. the application of a kind of dehydrobufotenine Foradil Aerolizer formoterol fumarate of claim 1 in preparation treatment lung tumors medicine.
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